Pharmaceutical compositions comprising glitazones and nrf2 activators

ABSTRACT

The invention relates to pharmaceutical compositions comprising PPAR agonists and Nrf2 activators and methods of using combinations of PPAR agonists and Nrf2 activators for treating diseases such as psoriasis, asthma, multiple sclerosis, inflammatory bowel disease, and arthritis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/553,219, now U.S. Pat. No. 11,484,530, which is a continuation ofU.S. application Ser. No. 15/356,766, filed Nov. 21, 2016, now U.S. Pat.No. 10,426,763, which is a continuation of U.S. application Ser. No.14/363,042, filed Jun. 5, 2014, now U.S. Pat. No. 9,504,679, which isthe U.S. national stage application of International Patent ApplicationNo. PCT/EP2012/074915, filed Dec. 10, 2012, which claims the benefit ofU.S. Provisional Patent Application No. 61/663,761, filed Jun. 25, 2012.

PCT/EP2012/074915 is a continuation-in-part of U.S. patent applicationSer. No. 13/654,632, filed Oct. 18, 2012, now abandoned, which claimsthe benefit of U.S. Provisional Patent Application No. 61/663,761, filedJun. 25, 2012.

STATEMENT REGARDING SEQUENCE LISTING

The Sequence Listing for this application is labeled “Seq-List.xml”which was created on Aug. 31, 2022 and is 2,223 bytes. The entirecontent of the sequence listing is incorporated herein by reference inits entirety.

Disclosed herein are pharmaceutical compositions comprising PPARagonists and Nrf2 activators (each an “agent” and together “agents”),and methods of using combinations of PPAR agonists and Nrf2 activatorsfor treating diseases such as psoriasis, asthma, multiple sclerosis,inflammatory bowel disease, and arthritis.

Peroxisome Proliferator Activated Receptors (PPARs) activatetranscription by binding to elements of DNA sequences, known asperoxisome proliferator response elements (PPRE), in the form ofheterodimers with retinoid X receptors (known as RXRs). Three subtypesof human PPARs have been identified and described: PPARα, PPARγ (PPARgamma) and PPARδ (or NUC1). PPARα is mainly expressed in the liver,while PPAR is ubiquitous. PPARγ is the most extensively studied of thethree subtypes See, e.g., “Differential Expression of PeroxisomeProliferator-Activated Receptor Subtypes During the Differentiation ofHuman Keratinocytes”, Michel Rivier et al., J. Invest. Dermatol., 111,1998, pp. 1116-1121, in which is listed a large number of bibliographicreferences relating to receptors of PPAR type. Mention may also be madeof “The PPARs: From Orphan Receptors to Drug Discovery”, Timothy M.Willson, Peter J. Brown, Daniel D. Sternbach and Brad R. Henke, J. Med.Chem., 2000, Vol. 43, pp. 527-550. It is suggested that PPARγ plays acritical role in regulating the differentiation of adipocytes, where itis greatly expressed. It also has a key role in systemic lipidhomeostasis.

It has been reported that the thiazolidinedione class of compounds (thegroup of so-called glitazones), including rosiglitazone, rosiglitazonemaleate, pioglitazone, pioglitazone hydrochloride, troglitazone andciglitazone and/or their salt forms, are potent and selective activatorsof PPAR gamma (so-called PPAR gamma agonists) and bind directly to thePPAR gamma receptor (J. M. Lehmann et al., J. Biol. Chem. 12953-12956,270 (1995)), providing evidence that PPAR gamma is a possible target forthe therapeutic actions of the thiazolidinediones. Since thisobservation, activation of this nuclear hormone receptor has been shownto have pleiotropic metabolic and nonhypoglycemic effects. Clinical useof the agents in the treatment of Type 2 diabetes mellitus (or noninsulin dependent diabetes mellitus (NIDDM)) is associated withsensitization to the glucose lowering effects of insulin as well aspotentiation of other biological actions of insulin in target tissues.When used as monotherapy, there are reports of fluid retention resultingin volume expansion and, in some patients, clinical edema. The incidenceof edema appears to be increased when both these agents are used incombination with insulin (Nesto R. W. et al, 2003, Circulation, 108,2941-2948). However, the mechanisms involved in these effects have notbeen well described but the nature of the presentation suggests anintegrated physiological response which includes an effect on renal saltand water balance. PPAR gamma receptors have been found in the renalcollecting duct (Guan Y. et al; 2001, Kidney Int. 60, 14-30) and,therefore, the PPAR gamma agonists might be involved directly in renaltubular metabolism or could have secondary effects on salt and waterhomeostasis. The PPAR gamma agonist pioglitazone has been suggested as atreatment of psoriasis in, e.g., British Journal of Dermatology 2005152, pp 176-198.

Nuclear factor erythroid-2 related factor 2 or Nuclear FactorE2p45-Related Factor (Nrf2) is a cap-and-collar basic leucine zippertranscription factor, regulates a transcriptional program that maintainscellular redox homeostasis and protects cells from oxidative insult(Rangasamy T, et al., J Clin Invest 114, 1248 (2004); Thimmulappa R K,et al. Cancer Res 62, 5196 (2002); So H S, et al. Cell Death Differ(2006)). NRF2 activates transcription of its target genes throughbinding specifically to the antioxidant-response element (ARE) found inthose gene promoters. The NRF2-regulated transcriptional programincludes a broad spectrum of genes, including antioxidants, such asγ-glutamyl cysteine synthetase modifier subunit (GCLm), γ-glutamylcysteine synthetase catalytic subunit (GCLc), heme oxygenase-1,superoxide dismutase, glutathione reductase (GSR), glutathioneperoxidase, thioredoxin, thioredoxin reductase, peroxiredoxins (PRDX),cysteine/glutamate transporter (SLC7A11) (7, 8)], phase IIdetoxification enzymes [NADP(H) quinone oxidoreductase 1 (NQO1), GST,UDP-glucuronosyltransferase (Rangasamy T, et al. J Clin Invest 114: 1248(2004); Thimmulappa R K, et al. Cancer Res 62: 5196 (2002)), and severalATP-dependent drug efflux pumps, including MRP1, MRP2 (Hayashi A, et al.Biochem Biophy Res Commun 310: 824 (2003)); Vollrath V, et al. Biochem J(2006)); Nguyen T, et al. Annu Rev Pharmacol Toxicol 43: 233 (2003)).

Interlinked with Nrf2 is KEAP1, which is a cytoplasmic anchor of Nrf2that also functions as a substrate adaptor protein for a Cul3-dependentE3 ubiquitin ligase complex to maintain steady-state levels of NRF2 andNRF2-dependent transcription (Kobayashi et al., Mol Cell Biol 24: 7130(2004); Zhang D, et al. Mol Cell Biol 24: 10491 (2004)). The KEAP1 geneis located at human chromosomal locus 19p13.2. The KEAP1 polypeptide hasthree major domains: (1) an N-terminal Broad complex, Tramtrack, andBric-a-brac (BTB) domain; (2) a central intervening region (IVR); and(3) a series of six C-terminal Kelch repeats (Adams J, et al. TrendsCell Biol 10:17 (2000)). The Kelch repeats of KEAP1 bind the Neh2 domainof Nrf2, whereas the IVR and BTB domains are required for theredox-sensitive regulation of Nrf2 through a series of reactivecysteines present throughout this region (Wakabayashi N, et al. ProcNatl Acad Sci USA 101: 2040 (2004)). KEAP1 constitutively suppressesNrf2 activity in the absence of stress. Oxidants, xenobiotics andelectrophiles hamper KEAP1-mediated proteasomal degradation of Nrf2,which results in increased nuclear accumulation and, in turn, thetranscriptional induction of target genes that ensure cell survival(Wakabayashi N, et al. Nat Genet. 35: 238 (2003)). Prothymosin α, anovel binding partner of KEAP1, has been shown to be an intranucleardissociator of the NRF2-KEAP1 complex and can upregulate the expressionof Nrf2 target genes (Karapetian R N, et al. Mol Cell Biol 25: 1089(2005)). Certain interactions between Nrf2 and PPAR gamma have beensuggested, e.g., in Am J Respir Crit Care Med 2010; 182:170-182.

Nrf2 activators according to the present invention are agents that afteradministration result in a stimulated and/or increased nucleartranslocation of Nrf2 protein and causes the subsequent increases ingene products that detoxify and eliminate cytotoxic metabolites. Nrf2activators according to the present invention may act directly on Nrf2,KEAP1, the NRF2-KEAP1 complex and/or otherwise. Nrf2 activators of thepresent invention may comprise a Michael addition acceptor, one or morefumaric acid esters, i.e., fumaric acid mono- and/or diesters which arepreferably selected from the group of monoalkyl hydrogen fumarates anddialkyl fumarates (such as monomethyl hydrogen fumarate, dimethylfumarate, monoethyl hydrogen fumarate, and diethyl fumarate), ethacrynicacid, bardoxolone methyl (methyl2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate), isothiocyanate such assulforaphane, 1,2-dithiole-3-thione such as oltipraz,3,5-di-tert-butyl-4-hydroxytoluene, 3-hydroxycoumarin, or apharmacologically active derivative or analog of the aforementionedagents.

Very preferred Nrf2 activators for use in combination with PPAR gammaagonists according to the present invention are bardoxolone methyl andfumaric acid esters.

Fumaric acid esters are approved in Germany for the treatment ofpsoriasis, are being evaluated in the United States for the treatment ofpsoriasis and multiple sclerosis, and have been proposed for use intreating a wide range of immunological, autoimmune, and inflammatorydiseases and conditions. FAEs and other fumaric acid derivatives havebeen proposed for use in treating a wide variety of diseases andconditions involving immunological, autoimmune, and/or inflammatoryprocesses including psoriasis (Joshi and Strebel, WO 1999/49858; U.S.Pat. No. 6,277,882; Mrowietz and Asadullah, Trends Mol Med 2005, 111(1),43-48; and Yazdi and Mrowietz, Clinics Dermatology 2008, 26, 522-526);asthma and chronic obstructive pulmonary diseases (Joshi et al., WO2005/023241 and US 2007/0027076); cardiac insufficiency including leftventricular insufficiency, myocardial infarction and angina pectoris(Joshi et al., WO 2005/023241; Joshi et al., US 2007/0027076);mitochondrial and neurodegenerative diseases such as Parkinson'sdisease, Alzheimer's disease, Huntington's disease, retinopathiapigmentosa and mitochondrial encephalomyopathy (Joshi and Strebel, WO2002/055063, US 2006/0205659, U.S. Pat. Nos. 6,509,376, 6,858,750, andU.S. Pat. No. 7,157,423); transplantation (Joshi and Strebel, WO2002/055063, US 2006/0205659, U.S. Pat. Nos. 6,359,003, 6,509,376, and7,157,423; and Lehmann et al, Arch Dermatol Res 2002, 294, 399-404);autoimmune diseases (Joshi and Strebel, WO 2002/055063, U.S. Pat. Nos.6,509,376, 7,157,423, and US 2006/0205659) including multiple sclerosis(MS) (Joshi and Strebel, WO 1998/52549 and U.S. Pat. No. 6,436,992; Wentand Lieberburg, US 2008/0089896; Schimrigk et al., Eur J Neurology 2006,13, 604-610; and Schilling et al., Clin Experimental Immunology 2006,145, 101-107); ischemia and reperfusion injury (Joshi et al., US2007/0027076); AGE-induced genome damage (Heidland, WO 2005/027899);inflammatory bowel diseases such as Crohn's disease and ulcerativecolitis; arthritis; and others (Nilsson et al., WO 2006/037342 andNilsson and Muller, WO 2007/042034). All of these indications anddiseases can be treated or prevented with the combination treatment ofthe present invention.

Fumaderm®, an enteric coated tablet containing a salt mixture ofmonoethyl fumarate and dimethylfumarate, which is rapidly hydrolyzed tomonomethyl fumarate, was approved in Germany in 1994 for the treatmentof psoriasis. Fumaderm® is dosed TID with 1-2 grams/day administered forthe treatment of psoriasis.

Biogen Idec Inc. is presently evaluating dimethyl fumarate under theproduct name BG-12 in the treatment of relapsing-remitting multiplesclerosis. The drug is under review with U.S. and European regulators.

Fumaric acid derivatives (Joshi and Strebel, WO 2002/055063, US2006/0205659, and U.S. Pat. No. 7,157,423 (amide compounds andprotein-fumarate conjugates); Joshi et al., WO 2002/055066 and Joshi andStrebel, U.S. Pat. No. 6,355,676 (mono and dialkyl esters); Joshi andStrebel, WO 2003/087174 (carbocyclic and oxacarbocylic compounds); Joshiet al., WO 2006/122652 (thiosuccinates); Joshi et al., US 2008/0233185(dialkyl and diaryl esters) and Nilsson et al., US 2008/0004344 (salts))have been developed in an effort to overcome the deficiencies of currenttherapy with fumaric acid esters. Controlled release pharmaceuticalcompositions comprising fumaric acid esters are disclosed by Nilsson andMüller, WO 2007/042034. Prodrugs are described by Nielsen and Bundgaard,J Pharm Sci 1988, 77(4), 285-298 and WO2010/022177.

DETAILED DESCRIPTION

Preferably, the term “alkyl” is specifically intended to include groupshaving any degree or level of saturation, i.e., groups havingexclusively single carbon-carbon bonds, groups having one or more doublecarbon-carbon bonds, groups having one or more triple carbon-carbonbonds, and groups having combinations of single, double, and triplecarbon-carbon bonds. Where a specific level of saturation is intended,the terms alkanyl, alkenyl, and alkynyl are used. In certainembodiments, an alkyl group can have from 1 to 20 carbon atoms (C1-20)in certain embodiments from 1 to 10 carbon atoms (C1-10), in certainembodiments from 1 to 8 carbon atoms (C1-8), in certain embodiments from1 to 6 carbon atoms (C1-6), in certain embodiments from 1 to 4 carbonatoms (C1-4), and in certain embodiments from 1 to 3 carbon atoms(C1-3). The term “alkoxy” refers to a group O-alkyl, wherein alkyl hasthe meaning indicated above. The term “perfluoroalkyl” refers to analkyl group wherein all hydrogen atoms have been replaced by fluoro.

“Treating” or “treatment” of any disease refers to reversing,alleviating, arresting, or ameliorating a disease or at least one of theclinical symptoms of a disease, reducing the risk of acquiring a diseaseor at least one of the clinical symptoms of a disease, inhibiting theprogress of a disease or at least one of the clinical symptoms of thedisease, or reducing the risk of developing a disease or at least one ofthe clinical symptoms of a disease. “Treating” or “treatment” alsorefers to inhibiting the disease, either physically (e.g., stabilizationof a discernible symptom), physiologically (e.g., stabilization of aphysical parameter), or both, and to inhibiting at least one physicalparameter that may or may not be discernible to the patient. In certainembodiments, “treating” or “treatment” refers to delaying the onset ofthe disease or at least one or more symptoms thereof in a patient whomay be exposed to or predisposed to a disease even though that patientdoes not yet experience or display symptoms of the disease.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a subject for treating a disease, or at leastone of the clinical symptoms of a disease, is sufficient to effect suchtreatment of the disease or symptom thereof. The “therapeuticallyeffective amount” may vary depending, for example, on the compound, thedisease and/or symptoms of the disease, the severity of the diseaseand/or symptoms of the disease or disorder, the age, weight, and/orhealth of the patient to be treated, and the judgment of the prescribingphysician. An appropriate amount in any given instance may beascertained by those skilled in the art or capable of determination byroutine experimentation.

“Therapeutically effective dose” refers to a dose that provideseffective treatment of a disease or disorder in a patient. Atherapeutically effective dose may vary from compound to compound, andfrom patient to patient, and may depend upon factors such as thecondition of the patient and the route of delivery. A therapeuticallyeffective dose may be determined in accordance with routinepharmacological procedures known to those skilled in the art.

Throughout the specification, the term “isolated Nrf2 activator”preferably refers to an Nrf2 activator which, if naturally occurring, issubstantially separated from other components and other molecules whichnaturally accompany the respective Nrf2 activator. The term embraces anNrf2 activator which has been removed from its naturally occurringenvironment or its natural state through purifying steps that separateother molecules naturally associated with it, e.g., by knownconventional methods such as chromatography, crystallization anddistillation. The term “isolated Nrf2 activator” preferably still allowsfor the Nrf2 activator to be in admixture with various amounts of water,such as up to about 20 weight %. The term “isolated Nrf2 activator”preferably excludes such Nrf2 activators which are still in theirnatural state, e.g., which are still contained in their source of originor parts thereof, such as a plant, irrespective of whether or not thissource of origin has been dried. Moreover, the term “isolated Nrf2activator” preferably refers to a natural or synthetically preparedmolecule which has a purity of above 70 weight %, preferably of above 80weight % and more preferably of above 90 weight %, such as about 95weight %, about 97 weight % or about 99 weight %, before beingformulated in a pharmaceutical composition, if so desired. In case theNrf2 activator is naturally occurring, e.g., as a natural product, it ispreferably an isolated Nrf2 activator, i.e., not in form of, e.g., anherbal preparation.

In case the PPAR gamma agonist is naturally occurring, e.g., as anatural product, it is preferably an isolated PPAR gamma agonist, i.e.,not in form of, e.g., an herbal preparation.

Reference is now made in detail to certain embodiments of compounds,compositions, and methods. The disclosed embodiments are not intended tobe limiting of the claims.

According to the present invention, strongly improved treatment resultsare obtained in the treatment of autoimmune and/or inflammatory diseaseswhen a PPAR agonist and preferably a PPAR gamma agonist and an Nrf2activator are used in the treatment of the disease in combination ascompared to treatment with a PPAR gamma agonist or an Nrf2 activatoralone. Co-administration of a PPAR gamma agonist and an Nrf2 activatoror an administration of a fixed dose combination of a PPAR gamma agonistand an Nrf2 activator results in an improved therapeutic effect, whichmay be a more than additive effect, compared to the administration of aPPAR gamma agonist or Nrf2 activators, respectively, as mono-therapy.

In particular, it has been found that the advantageous therapeuticresults in inflammatory and/or autoimmune diseases resulting from use ofcompounds such as dexamethasone, having both PPAR gamma agonistic andNrf2 activating effects, can be matched or even surpassed by thecombination treatment of the present invention, wherein at least twoindividual and different compounds, each having either PPAR gammaagonistic or Nrf2 activating effects, are employed. Thus, a combinationtreatment comprising at least one PPAR gamma agonist, which may have nosignificant or only a minor modulating or activating effect on Nrf2, andat least one Nrf2, which may have no significant or only a minormodulating or activating effect on PPAR gamma, result in improved andsynergistic therapeutic effects, as compared to the administration ofsuch PPAR gamma agonist or such Nrf2 activator, respectively, asmono-therapy. The synergistic effect is often more pronounced with suchcombinations, where the agents employed are predominantly either PPARgamma agonists or Nrf2 activators, which each have no significantactivity on the respective other target. Nevertheless, even in thosecases where one or both of the agents display significant PPAR gammaagonistic and Nrf2 activating effects at the same time, such as in thecase of dexamethasone and 15-deoxy-delta(12,14)-prostaglandin J(2)(15d-PGJ(2)), the combination treatment according to the presentinvention can lead to improved treatment results over the mono-therapy.A compound having dual effects on the targets PPAR gamma and Nrf2 isunlikely to show an ideally distributed effect on both targets fortherapeutic use. By applying the present invention each target can beaddressed individually and activated with suitable and appropriateconcentrations of the respective agents.

Thus, embodiments are preferred wherein at least one agent is not bothPPAR gamma agonist and Nrf2 activator at the same time.

Combination treatments and fixed dose combinations according to thepresent invention are preferred, which comprise at least two differentagents having either PPAR gamma agonistic or Nrf2 activating effects atthe concentration used in the combination.

The present invention relates to combination treatments, compositionscontaining the inventive combination of agents and related fixed-dosecombinations, wherein the PPAR agonist, such as the PPAR gamma agonist,and the Nrf2 activator are different compounds which preferably have adifferent chemical structure, e.g., have a difference in carbon atoms ofat least 3 carbon atoms, preferably at least 5 or at least 10 carbonatoms, and are not belonging to the same chemical class. Throughout thisspecification, the use of a singular also includes the plural, if notindicated otherwise.

Preferred PPAR agonists are compounds having a PPAR gamma agonisticeffect without significantly activating Nrf2. These are preferablycompounds having no ability to form covalent bonds with organic thiolgroups under physiological conditions, such as with glutathione. Thus,preferred PPAR gamma agonists are compounds that, contrary to, e.g.,15-deoxy-delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), cannot bindcovalently through, e.g., Michael addition reaction to the PPA receptor.Most preferred PPAR agonists are glitazones, glitazars and sartans.

PPAR agonists are PPAR activators (e.g., PPAR gamma agonists are PPARgamma activators). The definition of “PPAR agonist” and “PPAR gammaagonist” according to the present invention preferably includes suchagonists, i.e., compounds, that directly bind to the PPA receptor andhave an agonistic, i.e., activating effect, as well as so-calledphysiological PPAR agonists and physiological PPAR gamma agonists, whichdo not necessarily bind to the PPAR receptor, but result in anactivation of PPAR through other pathways, such as by increasing theconcentration of endogenous PPAR gamma agonist15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2).

A large number of natural and synthetic PPAR agonists are known (see,e.g., Michalik et al. (2006) Pharmacological Reviews 58:726-725; Gildeet al. (2003) Circulation Research 92(5):518-524; Peraza et al. (2005)Toxicological Sciences 90(2):269-295; and Desvergne & Wahli (1999)Endocrine Reviews 20(5):649-688). Some of these known agonists arespecific for a single PPAR isotype, while others target multiple PPARsubtypes. PPAR agonists are preferred, if the PPAR agonist more stronglyactivates PPAR gamma or PPAR gamma and PPAR alpha simultaneously thanother isoforms.

In one embodiment, the PPAR agonist may be selected from the groupconsisting of PPAR gamma agonists, such as glitazones, and dual PPARalpha/gamma agonists, such as glitazars. In yet further embodiments, theglitazone may be selected from the group consisting of troglitazone,pioglitazone, rosiglitazone, ciglitazone, englitazone, darglitazone,netoglitazone, isaglitazone, MC-555, balaglitazone, rivoglitazone, andthe like. In yet further embodiments, the glitazar may be selected fromthe group consisting of muraglitazar, naveglitazar, tesaglitazar,ragaglitazar, reglitazar and farglitazar. In yet further embodiments,PPAR agonists are selected from berberine, K-111, INT-131(2,4-dichloro-N-(3,5-dichloro-4-quinolin-3-yloxyphenyl)benzenesulfonamide),MBX-102 (metaglidasen;2-acetamidoethyl(2R)-2-(4-chlorophenyl)-2-[3-(trifluoromethyl)phenoxy]acetate),MBX-2044, FK614 (3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide), GSK-376501(1-[[3,5-bis(2-methoxyethoxy)phenyl]methyl]-3-(4-tert-butylphenyl)indolecarboxylic acid), GW 1929((2S)-2-(2-benzoylanilino)-3-[4-[2-[methyl(pyridinyl)amino]ethoxy]phenyl]propanoic acid), S26948 (dimethyl2-[[4-[2-(6-benzoyl-2-oxo-1,3-benzothiazol-3-yl)ethoxy]phenyl]methyl]propanedioate),psi-baptigenin and the like, such as those disclosed in U.S. Pat. Nos.5,002,953, 4,687,777 and 5,965,584. Pioglitazone and rosiglitazone arevery preferred and most preferred are pioglitazone hydrochloride androsiglitazone maleate.

In a further preferred embodiment of the present inventions, PPAR gammaagonists are selected from the class of statins or HMG-CoA reductaseinhibitors, preferably selected from atorvastatin, fluvastatin,lovastatin, pravastatin, rosuvastatin, simvastatin, mevastatin andpitavastatin. Statins are a class of drugs used to lower cholesterollevels by inhibiting the enzyme HMG-CoA reductase, which plays a centralrole in the production of cholesterol in the liver. Increasedcholesterol levels have been associated with cardiovascular diseases,and statins are therefore used in the prevention of these diseases.Statins have also been suggested for the treatment of multiple sclerosis(e.g., US 2004/0013643). Although statins are believed to activate PPARgamma only indirectly (Circ Res. 2007; 100:1442-1451), as physiologicalPPAR gamma agonists they are included in the definition of PPAR gammaagonists for the purposes of the present invention.

In a further preferred embodiment of the present invention, PPAR gammaagonists are selected from the chemical class of sartans, also known asangiotensin II receptor antagonists, angiotensin receptor blockers(ARBs) or AT1-receptor antagonists. Sartans, such as valsartan,losartan, azilsartan, irbesartan, olmesartan, telmisartan, candesartanand eprosartan, are a group of pharmaceuticals which modulate therenin-angiotensin-aldosterone system. Preferred sartans used in thepresent invention are selected from losartan, irbesartan, telmisartanand candesartan, which have shown to bind to and activate PPAR gamma(Drug Development Research 67:579-581, 2006). Treatment with sartans hasbeen suggested to improve multiple sclerosis. The sartans arepredominantly used in the treatment of hypertension, diabeticnephropathy (kidney damage due to diabetes) and chronic kidney diseaseas well as congestive heart failure and are also preferably employed forthese diseases and conditions when combined with Nrf2 activatorsaccording to the present invention.

In a further preferred embodiment of the present inventions, PPAR gammaagonists are selected from nonsteroidal anti-inflammatory drugs (NSAIDs)having PPAR gamma activating properties, preferably indomethacin,flufenamic acid, fenoprofen and ibuprofen (The Journal of BiologicalChemistry, vol. 272, no. 6, issue 7, pp. 3406-3410, 1997). NSAIDs areincluded in the definition of PPAR gamma agonists for the purposes ofthe present invention as they may bind directly to the PPAR or act as aphysiological PPAR gamma agonist. In one embodiment, NSAIDs other thanaspirin are preferred.

The group of NSAIDs comprises the following compounds: Salicylates, suchas aspirin (acetylsalicylic acid), diflunisal, and salsalate; propionicacid derivatives such as ibuprofen, dexibuprofen, naproxen, fenoprofen,ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, and loxoprofen;acetic acid derivatives such as indomethacin, sulindac, etodolac,ketorolac, diclofenac, and nabumetone; enolic acid (oxicam) derivativessuch as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, andisoxicam; fenamic acid derivatives (fenamates) such as mefenamic acid,meclofenamic acid, flufenamic acid, and tolfenamic acid; selective cox-2inhibitors (coxibs) such as celecoxib, rofecoxib, valdecoxib, parecoxib,lumiracoxib, etoricoxib, and firocoxib; sulphonanilides such asnimesulide; and others such as licofelone and lysine clonixinate.

Nrf2-activating compounds can be classified based on their chemicalstructures: Diphenols, Michael reaction acceptors, isothiocyanates,thiocarbamates, trivalent arsenicals, 1,2-dithiole-3-thiones,hydroperoxides, vicinal dimercaptans, heavy metals, and polyenes.Moreover, Nrf2 activators: (i) are all chemically reactive; (ii) arenearly all electrophiles; (iii) are mostly substrates for glutathionetransferases; and (iv) can all modify sulfhydryl groups by alkylation,oxidation, or reduction (PNAS Feb. 17, 2004 vol. 101 no. 7 2040-2045,Mol. Cell. Biol. 2009, 29(2):493). The activity of the compounds can beidentified by known methods.

Preferred Nrf2 activators are compounds without significant PPAR gammaagonistic effect. These are preferably compounds which may or may notbind covalently to the PPA receptor, but are not able to change theconformation of the PPAR and preferably the PPA gamma receptor to anextent that this would result in an activation of the PPA receptor.According to the present invention these preferred Nrf2 activators aresmall and of low molecular weight. These compounds preferably lack thestructural elements to bind to the PPA receptor non-covalently with theresult of a change of conformation and activation of the PPA receptor.In a preferred embodiment, the Nrf2 activators may be able to bindcovalently to the PPA receptor, e.g., via a Michael reaction with athiol group of the PPA receptor, without resulting in a conformationchange of the PPA receptor. Due to their limited size, however, thesepreferred Nrf2 activators may not prevent PPAR agonists, and inparticular PPAR gamma agonists, especially glitazones such aspioglitazone or rosiglitazone, from binding non-covalently to the PPAreceptor with the result of a conformation change.

In a very preferred example, the covalent binding of an Nrf2 activatorsuch as monomethyl hydrogen fumarate or dimethyl fumarate and thenon-covalent binding of a PPAR gamma agonist such as a glitazone, likepioglitazone or rosiglitazone, leads to synergistic and stronglyimproved therapeutic results.

In one embodiment, the preferred Nrf2 activators are selected fromorganic compounds having not more than one or two 5- or 6-memberedcarbocyclic rings or 5- or 6-membered heterocyclic rings having 1, 2 or3 N-, O- or S-atoms as ring atoms which may be fused to each other orpreferably no or only one carbocyclic or heterocyclic ring and/or lessthan 35, preferably less than 30, more preferably less than 25, mostpreferably less than 20, even less than 15 or less than 10 carbon atomsand/or have a molecular weight of less than 400, preferably less than300, most preferably less than 200 g/mol or less than 170 g/mol and areselected from the chemical classes of Michael reaction acceptors,phenols, diphenols, chalcones, isothiocyanates, thiocarbamates,quinones, naphthoquinones and 1,2-dithiole-3-thiones, wherein one ormore, preferably up to seven, H-atoms may be substituted by linear orbranched alkyl and perfluoroalkyl, such as methyl, ethyl,trifluoromethyl, halogen such as Br, Cl, F or I, hydroxy, alkoxy andperfluoroalkoxy, such as methoxy, ethoxy, trifluoromethoxy, cyano andnitro.

In cases where compounds of the chemical class of quinones are employedas Nrf2 activators, the respective hydroquinones can be usedalternatively. However, the respective oxidized form, i.e., therespective quinone, is preferred. The Nrf2 activity can be determinedaccording to e.g., JALA 2008; 13: 243-248. Bardoxolone methyl andderivatives are described in U.S. Pat. Nos. 8,129,429, 7,435,755 andUS2009/0060873. Amorphous bardoxolone methyl and suitable formulationsare disclosed in WO2010/093944.

Very preferred Nrf2 activators are capable of provoking or inducing astimulated and/or increased nuclear translocation of Nrf2 protein andare:

a) selected from the group of Michael reaction acceptors, phenols,diphenols, chalcones, isothiocyanates, thiocarbamates, quinones,naphthoquinones and 1,2-dithiole-3-thiones; and

b) contain less than 35 carbon atoms; and/or

c) have a molecular weight of less than 600 g/mol; and/or

d) contain no or not more than one or two fused or monocyclic 5- or6-membered carbocyclic or heterocyclic rings, having 1, 2 or 3 ringatoms selected from N, O or S.

In these preferred Nrf2 activators, one or more, preferably up to seven,H-atoms may be substituted preferably by linear or branched alkyl andperfluoroalkyl, such as methyl, ethyl, trifluoromethyl, halogen such asBr, Cl, F or I, hydroxy, alkoxy and perfluoroalkoxy, such as methoxy,ethoxy, trifluoromethoxy, cyano and nitro.

More preferred embodiments of these Nrf2 activators contain no ringsystem or only one or two rings, which may be carbocyclic and/orheterocyclic rings. Even more preferred Nrf2 activators contain lessthan 30, more preferably less than 25, most preferably less than 20,even less than 15 or less than 10 carbon atoms and/or have a molecularweight of less than 400 g/mol, more preferably less than 300 g/mol andmost preferably less than 200 g/mol or less than 170 g/mol. Furtherpreferred Nrf2 activators bind covalently to KEAP1 protein, preferablyvia an S-atom of the protein's amino acids.

Preferred Michael reaction acceptors are ketones, aldehydes, carboxylicacid esters and carboxylic acid amides, all of which are alpha, betaunsaturated.

More preferred Nrf2 activators are the compounds A to Z given below,including their tautomers and stereoisomers:

wherein the individual radicals have the meaning given below:

-   -   R¹ H, OH, Hal, CN, A, perfluoroalkyl, perfluoroalkoxy    -   R² H, OH, A, alkoxy, amino    -   R³ H, alkyl    -   R⁴ H, OH, alkyl, alkoxy    -   R⁵ H, OH, A, alkoxy    -   R⁶ H, A, alkoxy, aryl, het    -   R⁷ H, OH, A, alkoxy    -   R⁸ A    -   R⁹ Het    -   X O, NH, S    -   m 1, 2    -   n 1, 2, 3    -   Hal is F, Cl, Br or I, preferably F or Cl.

A is preferably alkyl, which denotes a straight or branched carbon chainhaving 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Alkylpreferably denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl or tert-butyl, or pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, or 1,1,2-or 1,2,2-trimethylpropyl. Alternatively, A denotes cycloalkyl having 3,4, 5, 6 or 7 carbon atoms or branched or linear alkyl having 2 to 12C-atoms, wherein one or more, preferably 1 to 7, H-atoms may be replacedby Hal, alkyl, alkoxy, cycloalkyl, phenyl, p-, m- or o-hydroxyphenyl,p-, m- or o-alkoxyphenyl, N(R³)₂, OH, CO₂H, or CF₃, and/or wherein oneor more, preferably 1 to 7, non-adjacent CH₂-groups may be replaced by—O—, —S—, —SO—, —NR³—, —CO—, —CO₂—, —CH═CH—S— and/or —CH═CH—. Cycloalkylpreferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl.

Alkoxy is preferably a group O-alkyl, wherein alkyl is defined as above.Preferably, alkoxy denotes a group —O—(CH₂)_(n)—CH₃, wherein n is 0, 1,2, 3 or 4, more preferably methoxy or ethoxy.

Perfluoroalkyl preferably denotes a straight or branched alkyl chainhaving 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, and whereinall hydrogen atoms are replaced by F atoms, preferably, for example,trifluoromethyl or pentafluoroethyl.

Perfluoroalkoxy is preferably a group O-perfluoroalkyl, whereinperfluoroalkyl is defined as above. Perfluoroalkoxy preferably denotesOCF₃.

Amino denotes preferably the group —NR′R″ where each R′, R″ isindependently hydrogen or alkyl. The group —NR′R″ can also form a cyclicgroup selected from piperidinyl, piperazinyl, pyrrolyl or morpholinyl,wherein one, two or three H atoms may be substituted by alkyl, such asmethyl. In one embodiment, amino denotes dialkylamino, wherein alkyl hasthe meaning given above and is preferably dimethylamino.

Aryl preferably denotes a monocyclic or bicyclic, aromatic carbocyclicring having 6 to 14 carbon atoms, which is unsubstituted ormonosubstituted, disubstituted or trisubstituted by F, Cl, Br, CF₃,OCF₃, NO₂, CN, alkyl, alkoxy, OH, amino, CO-amino, NHCO-alkyl, CO-alkyl,CO-alkoxy, SO₂-alkyl, or SO₂-amino. Most preferably, aryl denotesunsubstituted or monosubstituted phenyl.

Het preferably denotes, notwithstanding further substitutions, a 6- to14-membered monocyclic or bicyclic saturated, unsaturated or aromaticheterocyclic ring system containing 1 or 2 heteroatoms selected from N,O and S, which is unsubstituted or monosubstituted, disubstituted ortrisubstituted by F, Cl, Br, CF₃, OCF₃, NO₂, CN, alkyl, alkoxy, OH,amino, CO-amino, NHCO-alkyl, CO-alkyl, CO-alkoxy, SO₂-alkyl, orSO₂-amino. More preferably, Het is 2- or 3-furyl, 2- or 3-thienyl, 1-,2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl,2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-,4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, or 2-, 4-, 5- or6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl,1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4-or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl,indazolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-,4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-,4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-,4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxa-diazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, or 2-, 3-, 5-,6-, 7- or 8-2H-benzo-1,4-oxazinyl, furthermore preferably1,3-benzodioxol-5-yl, 1,4-benzodioxane-6-yl, 2,1,3-benzothiadiazol-4- or-5-yl or 2,1,3-benzoxadiazol-5-yl. The heterocyclic radicals may also bepartially or fully hydrogenated. Het can thus also denote, for example,2,3-dihydro-2-, -3-, 4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or-5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or-3-thienyl, 2,3-dihydro-1-, -2, -3, -4- or -5-pyrrolyl, 2,5-dihydro-1-,-2, -3, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2-or -4-imidazolyl, 2,3-dihydro-1-, -2, -3, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2, -3, -4, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxaneyl, 1,3-dioxane-2-, -4- or -5-yl, hexahydro-1-,-3- or -4-pyridazinyl, hexahydro-1-, -2, -4- or -5-pyrimidinyl, 1-, 2-or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2, -3, -4, -5, -6, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2, -3, -4, -5, -6, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or -6-yl,2,3-(2-oxomethylenedioxy)phenyl or 3,4-dihydro-2H-1,5-benzodioxepin-6-or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl or2,3-dihydro-2-oxofuranyl. Very preferably, heteroaryl is unsubstitutedor monosubstituted 2-pyridyl, pyrimidyl or imidazolyl.

R¹ is preferably H, OH, F, methyl, methoxy, or trifluoromethoxy.

R² is preferably H, OH, alkoxy, such as methoxy, or OCH₂CH₂-phenyl.

R³ is preferably H or alkyl, preferably H, methyl or tert-butyl.

R⁴ is preferably H, OH, or alkoxy, such as methoxy.

R⁵ is preferably H or A.

R⁶ is preferably H or Het.

R⁷ is preferably (CH₂)_(m)COR², (CH₂)_(m)COR², O(CH₂)_(m)COR² orO(CH₂)_(m)COR².

R⁸ is preferably allyl or a group selected from (C(R³)₂)_(q)S-alkyl or(C(R³)₂)_(q)SO-alkyl, wherein q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or12.

Preferred Nrf2 activators are selected from chalcone derivatives asdisclosed in J. Med. Chem., 2011, 54 (12), pp 4147-4159, such as2-trifluoromethyl-2′-methoxychalcone, auranofin (as contained in theFDA-approved drug Ridaura), ebselen, 1,2-naphthoquinone, cinnamicaldehyde, caffeic acid and its esters, curcumin, resveratrol,artesunate, tert-butylhydroquinone, and -quinone, (tBHQ, tBQ), vitaminsK1, K2 and K3, preferably menadione, fumaric acid esters, i.e., fumaricacid mono- and/or diester which is preferably selected from the group ofmonoalkyl hydrogen fumarate and dialkyl fumarate, such as monomethylhydrogen fumarate, dimethyl fumarate, monoethyl hydrogen fumarate, anddiethyl fumarate, 2-cyclopentenones, ethacrynic acid and its alkylesters, bardoxolone methyl (methyl2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate) (CDDO-Me, RTA 402), ethyl2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate,2-cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid (CDDO),1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyflimidazole (CDDO-Im),(2-cyano-N-methyl-3,12-dioxooleana-1,9(11)-dien-28 amide (CDDO-methylamide, CDDO-MA), isothiocyanate such as sulforaphane,1,2-dithiole-3-thione such as oltipraz, capsaicin,3,5-di-tert-butyl-4-hydroxytoluene, 3-hydroxycoumarin, cromolyn sodiumor any other salt thereof, nedocromil or its salt such as the sodiumsalt, 4-hydroxynonenal, 4-oxononenal, malondialdehyde, (E)-2-hexenal,capsaicin, allicin, allylisothiocyanate, 6-methylthiohexylisothiocyanate, 7-methylthioheptyl isothiocyanate, sulforaphane,8-methylthiooctyl isothiocyanate, corticosteroids, such asdexamethasone, 8-iso prostaglandin A2, alkyl pyruvate, such as methyland ethyl pyruvate, diethyl or dimethyl oxalopropionate,2-acetamidoacrylate, methyl or ethyl-2-acetamidoacrylate, hypoestoxide,parthenolide, eriodictyol, 4-Hydroxy-2-nonenal, 4-oxo-2-nonenal,geranial, zerumbone, aurone, isoliquiritigenin, xanthohumol,[10]-Shogaol, eugenol, 1′-acetoxychavicol acetate, allyl isothiocyanate,benzyl isothiocyanate, phenethyl isothiocyanate,4-(Methylthio)-3-butenyl isothiocyanate and 6-Methylsulfinylhexylisothiocyanate, ferulic acid and its esters, such as ferulic acid ethylester, and ferulic acid methyl ester, sofalcone, 4-methyl daphnetin,imperatorin, auraptene, poncimarin, bis[2-hydroxybenzylidene]acetones,alicylcurcuminoid, 4-bromo flavone, 3-naphthoflavone, sappanone A,aurones and its corresponding indole derivatives such asbenzylidene-indolin-2-ones, perillaldehyde, quercetin, fisetin, koparin,genistein, tanshinone IIA, BHA, BHT, PMX-290, AL-1, avicin D, gedunin,fisetin, andrographolide, [(±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile](TBE-31), 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile (TP-225),[(±)-(4b S,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile] (TBE-31), (TP-225),MCE-1, MCE5, ADT as referred to in Medicinal Research Reviews, 32, No.4, 687-726, 2012, gallic acid esters, such as alkyl esters, preferablyethyl gallate, n-propyl gallate and octyl gallate, orepigallocatechingallate, caffeic acid esters such as alkyl esters or itsphenethyl ester, Coenzyme Q10 (Ubiquinone, Ubidecarenone), and therespective quinone or hydroquinone forms of the aforementioned quinoneand hydroquinone derivatives and stereoisomers, tautomers orpharmacologically active derivatives of the aforementioned agents, suchas the respective phenyl esters, alkyl esters, and alkanoyl esters andbenzoyl ethers, phenyl ethers and alkyl ethers.

Very preferred Nrf2 activators are selected from carnosic acid,2-naphthoquinone, cinnamic aldehyde, caffeic acid and its esters,curcumin, resveratrol, artesunate, tert-butylhydroquinone, vitamins K1,K2 and K3, fumaric acid esters, i.e., fumaric acid mono- and/or diester,which is preferably selected from the group of monoalkyl hydrogenfumarate and dialkyl fumarate, such as monomethyl hydrogen fumarate,dimethyl fumarate, monoethyl hydrogen fumarate, and diethyl fumarate,isothiocyanate such as sulforaphane, 1,2-dithiole-3-thione such asoltipraz, capsaicin, 3,5-di-tert-butyl-4-hydroxytoluene,3-hydroxycoumarin, 4-hydroxynonenal, 4-oxononenal, malondialdehyde,(E)-2-hexenal, capsaicin, allicin, allylisothiocyanate,6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate,sulforaphane, 8-methylthiooctyl isothiocyanate, 8-iso prostaglandin A2,alkyl pyruvate, such as methyl and ethyl pyruvate, diethyl or dimethyloxalopropionate, 2-acetamidoacrylate, methyl orethyl-2-acetamidoacrylate, hypoestoxide, parthenolide, eriodictyol,4-Hydroxy-2-nonenal, 4-oxo-2-nonenal, geranial, zerumbone, aurone,isoliquiritigenin, xanthohumol, [10]-Shogaol, eugenol,l′-acetoxychavicol acetate, allyl isothiocyanate, benzyl isothiocyanate,phenethyl isothiocyanate, 4-(Methylthio)-3-butenyl isothiocyanate and6-Methylsulfinylhexyl isothiocyanate and the respective quinone orhydroquinone forms of the aforementioned quinone and hydroquinonederivatives and stereoisomers, tautomers or pharmacologically activederivatives of the aforementioned agents. Very preferred Nrf2 activatorsare Michael reaction acceptors such as dimethyl fumarate, monomethylhydrogen fumarate isothiocyanates and 1,2-dithiole-3-thiones. In anotherembodiment, very preferred Nrf2 activators are selected from monomethylhydrogen fumarate, dimethyl fumarate, oltipraz, 1,2-naphthoquinone,tert-butylhydroquinone, methyl and ethyl pyruvate,3,5-di-tert-butyl-4-hydroxytoluene, diethyl and dimethyloxalopropionate, hypoestoxide, parthenolide, eriodictyol,4-hydroxy-2-nonenal, 4-oxo-2-nonenal, geranial, zerumbone, aurone,isoliquiritigenin, xanthohumol, [10]-Shogaol, eugenol,1′-acetoxychavicol acetate, allyl isothiocyanate, benzyl isothiocyanate,phenethyl isothiocyanate, 4-(Methylthio)-3-butenyl isothiocyanate and6-Methylsulfinylhexyl isothiocyanate.

Another group of preferred Nrf2 activators comprises fumaric acidesters, bardoxolone methyl (methyl2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, CDDO-Me, RTA 402), ethyl2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate,2-cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid (CDDO),1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyflimidazole (CDDO-Im),2-cyano-N-methyl-3,12-dioxooleana-1,9(11)-dien-28 amide (CDDO-methylamide, CDDO-MA), [(±)-(4b S, 8aR, 10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile](TBE-31), 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile (TP-225),3-tert-butyl-4-hydroxyanisole, 2-tert-butyl-4-hydroxyanisole (BHA),tert-butylquinone (tBQ), tert-butylhydroquinone (tBHQ),3,5-di-tert-butyl-4-hydroxytoluene (BHT),2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadien-1-one (2,6-Di-tert-butylquinone methide, BHT-quinone methide), ethoxyquin, gallic acid esters,alpha lipoic acid and its esters, such as alkyl esters, preferablylipoic acid ethyl ester, curcumin, resveratrol, menadione, cinnamicaldehyde, cinnamic acid esters, caffeic acid esters, cafestol, kahweol,lycopene, carnosol, sulforaphane, oltipraz, capsaicin(8-Methyl-N-vanillyl-trans-6-nonenamide),5-(4-methoxy-phenyl)-1,2-dithiole-3-thione (ADT), sulfasalazine,5-aminosalicylic acid (mesalamine), 5-amino-2-hydroxy-benzoic acid4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenyl ester (ATB-429), allicin,allylisothiocyanate, zerumbone, phenethyl isothiocyanate, benzylisothiocyanate, and 6-methylsulfinylhexyl isothiocyanate as well asalkyl and alkanoyl esters, alkyl ethers, stereoisomers, tautomers andsalts of the aforementioned agents.

In an even more preferred embodiment of the present invention, the Nrf2activator is selected from the group of fumaric acid esters,3-tert-butyl-4-hydroxyanisole, 2-tert-butyl-4-hydroxyanisole (BHA),tert-butylquinone (tBQ), tert-butylhydroquinone (tBHQ),3,5-di-tert-butyl-4-hydroxytoluene (BHT),2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadien-1-one(2,6-Di-tert-butylquinone methide, BHT-quinone methide), ethoxyquin,gallic acid esters, curcumin, resveratrol, menadione, cinnamic aldehyde,cinnamic acid esters, caffeic acid esters, cafestol, kahweol, lycopene,carnosol, sulforaphane, oltipraz,5-(4-methoxy-phenyl)-1,2-dithiole-3-thione (ADT), sulfasalazine, 5-aminosalicylic acid (mesalamine), 5-amino hydroxy-benzoic acid4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenyl ester (ATB-429), allicin,allylisothiocyanate, zerumbone, phenethyl isothiocyanate, benzylisothiocyanate, a n d 6-methylsulfinylhexyl isothiocyanate as well asalkyl and alkanoyl esters, alkyl ethers, stereoisomers, tautomers andsalts of the aforementioned agents. These preferred aforementioned Nrf2activators have no or no significant agonistic activity or significanteffect on PPAR gamma.

In a further embodiment of the present invention, the Nrf2 activator isauranofin. Auranofin is preferably used according to the invention witha glitazone, more preferably pioglitazone or rosiglitazone.

In a further embodiment of the present invention, the Nrf2 activator isselected from sulfasalazine or 5-aminosalicylic acid (mesalamine).Sulfasalazine or 5-aminosalicylic acid (mesalamine) is preferably usedaccording to the invention with a glitazone, more preferablypioglitazone or rosiglitazone.

It is particularly advantageous that the use of the PPAR gamma agonistand the Nrf2 activator according to the present invention may allow forthe maximum dosage of each agent when used in mono-therapy, which resultin maximal therapeutic effect. No or only very limited increase inadverse side effects known for the individual PPAR gamma agonist or theNrf2 activator can be observed. It may also be advantageous to reducethe dose of one or both of the agents employed in the combinationtreatment of the present invention. Thus, side effects that may beobserved in mono-therapy with the agents may be avoided or reduced.Throughout the specification, the term “pharmacologically activederivatives” preferably denotes salts, amides and esters, such asalkylesters, including methyl and ethyl esters, of pharmacologicallyactive acids and alkanoic acid esters and ethers of pharmacologicallyactive alcohols, such as acetic acid esters and methyl ethers, as wellas alkanoic acid amides of pharmacologically active amines, such as therespective acetic acid amides.

The combination treatment of the present invention can be furthercombined with treatments and medicaments that are generally used in thevarious indications as standard treatments. In the treatment of multiplesclerosis, for example, the combination treatment of the presentinvention can be further combined with interferon, such as interferonbeta 1b or interferon beta 1a (Rebif, Avonex) or glatiramer acetate(Copaxone), a sphingosine 1-phosphate receptor modulator, such asFingolimod (Gilenya) and/or methotrexate. The combination treatment ofthe present invention can be further combined with RXR specific ligands,such as 9-cis-retinoic acid (RA), in order to obtain even furtherimproved results, particularly in the treatment of psoriasis.

The combination therapy of the present invention can, especially for thetreatment of Parkinson's disease, be further combined with establishedtherapeutic agents well-known in the art for the disease, such aslevodopa, usually combined with a dopa decarboxylase inhibitor, such ascarbidopa or benserazide or a COMT inhibitor, such as entacapone,tolcapone or nitecapone. Moreover, the combination therapy of thepresent invention can be further combined with dopamine agonists, suchas bromocriptine, pergolide, pramipexole, ropinirole, piribedil,cabergoline, apomorphine, lisuride or rotigotine and MAO-B inhibitors,such as selegiline or rasagiline.

The combination therapy according to the present invention may beadministered as a simultaneous or sequential regimen, also referred toas co-administration. When administered sequentially, the combinationmay be administered in two or more administrations. It is also possibleto combine any PPAR gamma agonist with an Nrf2 activator in a unitarydosage form for simultaneous or sequential administration to a patient.

In general, for compositions containing fumaric acid esters, anadministration twice daily (BID) or thrice daily (TID) is preferred. Thedosages of the individual agents are adjusted accordingly.

Co-administration of a PPAR gamma agonist with an Nrf2 activatoraccording to the invention generally and preferably refers tosimultaneous or sequential administration of a PPAR gamma agonist and anNrf2 activator, such that therapeutically effective amounts of the PPARgamma agonist and the Nrf2 activator are both present at the same timein the body of the patient.

Co-administration includes simultaneous administration andadministration of an agent according to the invention before or afteradministration of the other agent, for example, administration of bothagents according to the invention within seconds, minutes, or hours. Inone embodiment, the first agent is administered, followed, after aperiod of hours (e.g., 0.25-12 hours, preferably 0.5 to 3 hours, mostpreferably 1 to 2 hours), by administration of the second agent.

The combination therapy and co-administration according to the inventionfrequently provides “synergy” and “synergistic effect”, i.e., thetherapeutic effect achieved when the PPAR gamma agonist and the Nrf2activator are used together is more than additive, i.e., greater thanthe sum of the effects that result from using each agent alone.

An appropriate dose of a PPAR agonist and an Nrf2 activator orpharmaceutical composition comprising a PPAR agonist and an Nrf2activator for use in the present invention, may be determined accordingto any one of several well-established protocols. For example, animalstudies such as studies using mice, rats, dogs, and/or monkeys may beused to determine an appropriate dose of a pharmaceutical compound.Results from animal studies may be extrapolated to determine doses foruse in other species, such as humans.

In general, a preferred PPAR gamma agonist is administered incombination with a preferred Nrf2 activator according to the invention,preferably orally, in daily dosages of 0.01 mg to 50 mg per kg bodyweight, dependent on the activity and safety of the respective PPARgamma agonist. If not indicated otherwise, the dosages given above andbelow reflect the amount of free base of the PPAR gamma agonist, even ifused in form of the maleate or another acid addition salt.

Preferred Nrf2 activators are bardoxolone methyl and dialkyl fumaratessuch as dimethyl fumarate and diethyl fumarate.

The dialkyl fumarates to be used according to the invention are preparedby processes known in the art (see, for example, EP 0 312 697).

Preferably, the active ingredients, i.e., the agents, are used forpreparing oral preparations in the form of tablets, micro-tablets,pellets or granulates, optionally in capsules or sachets. Preparationsin the form of micro-tablets or pellets, optionally filled in capsulesor sachets, are preferred and are also a subject matter of theinvention. According to a preferred embodiment, the size or the meandiameter, respectively, of the pellets or micro-tablets is in the rangeof 300 to 2,000 μm, especially in the range of 500 to 1,000 μm.

The oral preparations may be provided with an enteric coating. Capsulesmay be soft or hard gelatine capsules.

The dialkyl fumarates used according to the invention may be used aloneor as a mixture of several compounds, optionally in combination with thecustomary carriers and excipients. The amounts to be used are selectedin such a manner that the preparations, such as tablets, obtainedcontain the active ingredient in an amount corresponding to 10 to 300 mgof fumaric acid per dosage unit.

Preferred preparations according to the invention contain a total amountof 10 to 300 mg of dimethyl fumarate and/or diethyl fumarate.

Fixed-dose combinations of a PPAR agonist and preferably a PPAR gammaagonist with an Nrf2 activator are preferred. Fixed-dose combinations ofrosiglitazone with dimethyl fumarate and rosiglitazone with bardoxolonemethyl are particularly preferred. Fixed-dose combinations ofpioglitazone with dimethyl fumarate and rosiglitazone with bardoxolonemethyl are particularly preferred.

In particular, rosiglitazone is preferably administered according to theinvention in t h e form of its maleate in daily dosages of 0.01 to 0.2mg per kg body weight, more preferably in daily dosages of 0.02 to 0.16mg per kg body weight and most preferably in daily dosages of 0.025 mgto 0.14 mg per kg body weight, such as in daily dosages of 0.03 mg, 0.06mg or 0.12 mg per kg body weight. Daily oral dosages of 2 mg, 4 mg and 8mg rosiglitazone per patient are particularly preferred.

In particular, pioglitazone is preferably administered according to theinvention in the form of its hydrochloride in daily dosages of 0.05 to 1mg per kg body weight, more preferably in daily dosages of 0.1 to 0.8 mgper kg body weight and most preferably in daily dosages of 0.15 mg to0.7 mg per kg body weight, such as in daily dosages of about 0.2 mg,about 0.4 mg or about 0.6 mg per kg body weight. Daily oral dosages ofabout 15 mg, about 30 mg and about 45 mg pioglitazone per patient areparticularly preferred.

In particular, ciglitazone or troglitazone are preferably administeredaccording to the invention in daily dosages of 1 to 20 mg per kg bodyweight, more preferably in daily dosages of 2 to 15 mg per kg bodyweight and most preferably in daily dosages of 3 mg to 10 mg per kg bodyweight. Oral dosages are particularly preferred.

In general, a preferred Nrf2 activator is administered in combinationwith a preferred PPAR gamma agonist, preferably orally, in daily dosagesof 0.1 mg to 20 mg per kg body weight, dependent on the activity andsafety of the respective Nrf2 activator.

In particular, bardoxolone methyl is preferably administered accordingto the invention in daily dosages of 0.1 to 3 mg per kg body weight,more preferably in daily dosages of 0.2 to 2.5 mg per kg body weight andmost preferably in daily dosages of 0.3 mg to 2.2 mg per kg body weight,such as in daily dosages of about 0.35 mg, about 1.1 mg or about 2 mgper kg body weight. Daily oral dosages of about 25 mg, about 75 mg andabout 150 mg bardoxolone methyl per patient are particularly preferred.

In particular, dimethyl fumarate is preferably administered according tothe invention in daily dosages of 1 to 20 mg per kg body weight, morepreferably in daily dosages of 2 to 15 mg per kg body weight and mostpreferably in daily dosages of 3 mg to 12 mg per kg body weight, such asin daily dosages of about 3.4 mg, about 7 mg or about 10 mg per kg bodyweight. Daily oral dosages of about 240 mg, about 480 mg and about 720mg dimethyl fumarate per patient are particularly preferred.

The ratio between the dosages of the PPAR gamma agonist and the Nrf2activator used in the combinations according to the present inventiondepends on the activity of the particular PPAR gamma agonist and Nrf2activator selected.

Daily oral dosages of 2 mg, 4 mg and 8 mg rosiglitazone per patient areparticularly preferred.

Daily oral dosages of about 20 mg, about 25 mg, about 75 mg and about150 mg bardoxolone methyl per patient are particularly preferred. Incase bardoxolone methyl is employed in amorphous form, daily dosages ofabout 20 mg per patient are most preferred.

Daily oral dosages of about 120 mg, about 240 mg, about 360 mg, about480 mg, about 600 mg and about 720 mg dimethyl fumarate per patient areparticularly preferred.

If the Nrf2 activator is dimethyl fumarate, once or twice daily dosingis preferred.

Preferred dosage forms and in particular oral dosage forms such astablets or capsules may contain:

For daily administration, dosage forms such as tablets or capsules maycontain preferably about 2 mg rosiglitazone and about 25 mg bardoxolonemethyl or about 2 mg rosiglitazone and about 75 mg bardoxolone methyl orabout 2 mg rosiglitazone and about 150 mg bardoxolone methyl or about 4mg rosiglitazone and about 25 mg bardoxolone methyl or about 4 mgrosiglitazone and about 75 mg bardoxolone methyl or about 4 mgrosiglitazone and about 150 mg bardoxolone methyl or about 8 mgrosiglitazone and about 25 mg bardoxolone methyl or about 8 mgrosiglitazone and about 75 mg bardoxolone methyl or about 8 mgrosiglitazone and about 150 mg bardoxolone methyl. Most preferably, adosage form may contain about 8 mg rosiglitazone and about 150 mgbardoxolone methyl.

For administration three times daily, preferred dosage forms such astablets or capsules may contain about 0.7 mg, preferably about 0.67 mg,rosiglitazone and 240 mg dimethyl fumarate or about 1.3 mg, preferablyabout 1.33 mg, rosiglitazone and about 240 mg dimethyl fumarate or about2.7 mg, preferably about 2.67 mg, rosiglitazone and about 240 mgdimethyl fumarate or about 0.7 mg, preferably about 0.67 mg,rosiglitazone and 120 mg dimethyl fumarate or about 1.3 mg, preferablyabout 1.33 mg, rosiglitazone and about 120 mg dimethyl fumarate or about2.7 mg, preferably about 2.67 mg, rosiglitazone and about 120 mgdimethyl fumarate. Most preferably, a dosage form may contain about 2.7mg, preferably about 2.67 mg, rosiglitazone and about 240 mg dimethylfumarate.

For administration two times daily, preferred dosage forms such astablets or capsules may contain about 1 mg rosiglitazone and about 240mg dimethyl fumarate or about 2 mg rosiglitazone and about 240 mgdimethyl fumarate or about 4 mg rosiglitazone and about 240 mg dimethylfumarate.

For daily administration, dosage forms such as tablets or capsules maycontain preferably about 15 mg pioglitazone and about 25 mg bardoxolonemethyl or about 15 mg pioglitazone and about 75 mg bardoxolone methyl orabout 15 mg pioglitazone and about 150 mg bardoxolone methyl or about 30mg pioglitazone and about 25 mg bardoxolone methyl or about 30 mgpioglitazone and about 75 mg bardoxolone methyl or about 30 mgpioglitazone and about 150 mg bardoxolone methyl or about 45 mgpioglitazone and about 25 mg bardoxolone methyl or about 45 mgpioglitazone and about 75 mg bardoxolone methyl or about 45 mgpioglitazone and about 150 mg bardoxolone methyl. Most preferably, adosage form may contain about 45 mg pioglitazone and about 150 mgbardoxolone methyl.

For administration three times daily, preferred dosage forms such astablets or capsules may contain about 5 mg pioglitazone and 240 mgdimethyl fumarate or about 10 mg pioglitazone and about 240 mg dimethylfumarate or about 15 mg pioglitazone and about 240 mg dimethyl fumarateor about 5 mg pioglitazone and 120 mg dimethyl fumarate or about 10 mgpioglitazone and about 120 mg dimethyl fumarate or about 15 mgpioglitazone and about 120 mg dimethyl fumarate. Most preferably, adosage form may contain about 15 mg pioglitazone and about 240 mgdimethyl fumarate.

For administration two times daily, preferred dosage forms such astablets or capsules may contain about 7.5 mg pioglitazone and about 240mg dimethyl fumarate or about 15 mg pioglitazone and about 240 mgdimethyl fumarate or about 22.5 mg pioglitazone and about 240 mgdimethyl fumarate.

Moreover, pharmaceutical compositions according to the present inventionare preferred which comprise as a PPAR gamma agonist about 5 mg, about7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 22.5 mg or about 25mg of pioglitazone. Also, pharmaceutical compositions according to thepresent invention are preferred which comprise as a PPAR gamma agonistabout 0.7 mg, about 1 mg, about 1.3 mg, about 2 mg, about 2.7 mg, about3 mg, about 3.5 mg, about 4 or about 5 mg of rosiglitazone.

Pharmaceutical compositions according to the present invention arepreferred which comprise about 120 mg, about 200 mg or about 240 mg ofdimethyl fumarate.

In particular, atorvastatin is preferably administered according to theinvention in the form of its calcium salt in daily oral dosages of about10, about 20, about 40 or about 80 mg per patient. Preferably,atorvastatin is combined in the above dosages with dimethyl fumarate indosages of about 120, about 240, about 360, about 480 or about 720 mgper day. Most preferred are combinations containing about 20 mg or about40 mg of atorvastatin in the form of its calcium salt, and about 240 mgdimethyl fumarate.

In a further embodiment, atorvastatin is combined in the above dosageswith bardoxolone methyl in its amorphous form in dosages of about 20 mgper day. Most preferred are combinations containing about 40 mg or about80 mg of atorvastatin in the form of its calcium salt, and about 20 mgbardoxolone methyl in its amorphous form.

In particular, losartan is preferably administered according to theinvention in daily oral dosages of about 25, about 50, about 75 or about100 mg per patient. Preferably, losartan is combined in the abovedosages with dimethyl fumarate in dosages of about 120, about 240, about360, about 480 or about 720 mg per day. Most preferred are combinationscontaining about 25 mg or about 50 mg of losartan, and about 240 mgdimethyl fumarate. The combination is preferably administered twicedaily. The combination treatments of sartans and preferably losartan,irbesartan, telmisartan and candesartan with Nrf2 activators such asdimethyl fumarate and bardoxolone methyl are particularly effective forthe treatment of diabetic nephropathy (kidney damage due to diabetes)and chronic kidney disease, and also for the treatment of multiplesclerosis.

In a further example, losartan is combined in the above dosages withbardoxolone methyl in its amorphous form in dosages of about 20 mg perday. Most preferred are combinations containing about 25 mg or about 50mg of losartan, and about 20 mg bardoxolone methyl in its amorphousform. The combination is preferably administered once daily.

In particular, ibuprofen is preferably administered according to theinvention in daily dosages that are applicable to monotherapy withibuprofen, such as about 600 mg, about 800 mg, about 1200 mg or about2400 mg per patient. Most preferred are combinations containing about600 mg of ibuprofen and about 240 mg dimethyl fumarate. The combinationis preferably administered twice daily.

In a further example, ibuprofen is combined in the above dosages withbardoxolone methyl in its amorphous form in dosages of about 20 mg perday. Most preferred are combinations containing about 800 mg ofibuprofen, and about 20 mg bardoxolone methyl in its amorphous form. Thecombination is preferably administered once daily.

Preferred ratios between rosiglitazone and dimethyl fumarate areselected from 1/20 to 1/400 (w/w, rosiglitazone/dimethyl fumarate),preferably from 1/25 to 380, more preferably from 1/28 to 1/360. Mostpreferably the ratios are about 1/30, about 1/45, such as about 1/44.4,about 1/60, about 1/90, such as about 1/88.9 or about 1/92.3, about1/120, about 1/180, such as 1/171.4 or 1/184.6, about 1/240, or about1/340, such as about 1/342.9.

Preferred ratios between pioglitazone and dimethyl fumarate are selectedfrom 1/3 to 1/60 (w/w, pioglitazone/dimethyl fumarate), preferably from1/4 to 1/55, more preferably from 1/5 to 1/52. Most preferably theratios are about 1/5.3, about 1/8, about 1/10, such as 1/10.7, about1/12, about 1/16, about 1/24, about 1/32, or about 1 to 48.

In general, ratios between rosiglitazone and bardoxolone methyl areselected from 1/1 to 1/100 (w/w, rosiglitazone/bardoxolone methyl),preferably from 1/1.5 to 1/80, more preferably from 1/2 to 1/75. Mostpreferably the ratios are about 1/2.5, such as about 1/3.1, about 1/5,such as 1/6.3, about 1/10, such as about 1/9.4 or about 1/12.5, about1/20, such as 1/18.8, about 1/40, such as about 1/37.5, or about 1/70,such as about 1/75.

In general, ratios between pioglitazone and bardoxolone methyl areselected from 1/0.1 to 1/20 (w/w, pioglitazone/bardoxolone methyl),preferably from 1/0.3 to 1/15, more preferably from 1/0.4 to 1/12. Mostpreferably the ratios are about 1/0.5, such as about 1/0.4, about 1/0.6,about 1/0.7, or about 1/0.8, about 1/2, such as about 1/1.7 or about1/2.5, about 1/3, such as about 1/3.3, about 1/5 or about 1/10.

In preferred embodiments of the present invention, amorphic bardoxolonemethyl is employed more preferably in a pharmaceutical formulationcomprising amorphous bardoxolone methyl, preferably obtained asspray-dried dispersion with a glass-forming excipient, such asmethacrylic acid copolymer Type C, USP, e.g., in a 4/6 weight ratio ofbardoxolone methyl to methacrylic acid copolymer Type C, USP (Eudragit),more preferably admixed with particles comprised of at least onehydrophilic binder, such as hydroxypropylmethylcellulose, according toUS2012/022156. Preferred compositions of bardoxolone methyl according tothe present invention also contain a surface active ingredient, such assodium lauryl sulfate, preferably in amounts of about 1 to 5 weight %,preferably about 3%, such as 2.73%, of the total composition.

In preferred embodiments, amorphous bardoxolone methyl is administeredaccording to the invention in daily dosages of 0.05 to 1 mg per kg bodyweight, more preferably in dosages of 0.1 to 0.8 mg per kg body weightand most preferably in dosages of 0.2 mg to 0.6 mg per kg body weight,such as in daily dosages of about 0.15 mg, about 0.25 mg or about 0.35mg per kg body weight. Daily oral dosages of about 10 mg, about 20 mg,and about 30 mg bardoxolone methyl per patient are particularlypreferred.

For daily administration of amorphous bardoxolone methyl, the followingdosages are employed per patient: about 2 mg rosiglitazone and about 10mg bardoxolone methyl or about 2 mg rosiglitazone and about 20 mgbardoxolone methyl or about 2 mg rosiglitazone and about 30 mgbardoxolone methyl or about 4 mg rosiglitazone and about 10 mgbardoxolone methyl or about 4 mg rosiglitazone and about 20 mgbardoxolone methyl or about 4 mg rosiglitazone and about 30 mgbardoxolone methyl or about 8 mg rosiglitazone and about 10 mgbardoxolone methyl or about 8 mg rosiglitazone and about 20 mgbardoxolone methyl or about 8 mg rosiglitazone and about 30 mgbardoxolone methyl. Most preferably, about 8 mg rosiglitazone and about20 mg bardoxolone methyl are employed. In particular it is preferred ifthe above amounts are used in a fixed dose combination, i.e., in a solidoral dosage form.

Alternatively, for daily administration of amorphous bardoxolone methyl,the following dosages are employed per patient: about 15 mg pioglitazoneand about 10 mg bardoxolone methyl or about 15 mg pioglitazone and about20 mg bardoxolone methyl or about 15 mg pioglitazone and about 30 mgbardoxolone methyl or about 30 mg pioglitazone and about 10 mgbardoxolone methyl or about 30 mg pioglitazone and about 20 mgbardoxolone methyl or about 30 mg pioglitazone and about 30 mgbardoxolone methyl or about 45 mg pioglitazone and about 10 mgbardoxolone methyl or about 45 mg pioglitazone and about 20 mgbardoxolone methyl or about 45 mg pioglitazone and about 30 mgbardoxolone methyl. Most preferably, about 45 mg pioglitazone and about20 mg bardoxolone methyl are employed. Most preferably, about 8 mgrosiglitazone and about 20 mg bardoxolone methyl are employed. Inparticular it is preferred if the above amounts are used in a fixed dosecombination, i.e., in a solid oral dosage form.

In preferred embodiments of the present invention, where bardoxolonemethyl is employed in its amorphous form, preferred ratios betweenrosiglitazone and bardoxolone methyl are from 1/1 to 1/20 (“I” indicates“to” throughout this application, when a ratio is concerned, w/w,rosiglitazone/bardoxolone methyl), preferably from 1/1.1 to 1/17, morepreferably from 1/1.2 to 1/16. Most preferably the ratios are about1/1.3, such as about 1/1.25, about 1/2.5, about 1/3.5, such as 1/3.75,about 1/5, about 7.5, or about 1/10.

In further preferred embodiments of the present invention, wherebardoxolone methyl is employed in its amorphous form, preferred ratiosbetween pioglitazone and bardoxolone methyl are from 1/0.1 to 1/3 (w/w,pioglitazone/bardoxolone methyl), preferably from 1/0.15 to 1/2.5, morepreferably from 1/0.2 to 1/2.2. Most preferably the ratios are about1/0.2, such as about 1/0.22, about 1/0.3, such as about 1/0.33, about1/0.4, such as about 1/0.44, about 1/0.7, such as about 1/0.67, about1/1 or about 1/2.

Dosage forms and in particular oral dosage forms such as tablets orcapsules containing both a PPAR gamma agonist and an Nrf2 activator in afixed dose combination comprising the above compositions in the givenratios and especially those containing amorphic bardoxolone methyl arepreferred.

Fixed dose combinations, such as tablets containing the activeingredients in the above amounts and ratios, are most preferred.

Pharmaceutical compositions provided by the present disclosure maycomprise a therapeutically effective amount of a PPAR gamma agonist andan Nrf2 activator together with a suitable amount of one or morepharmaceutically acceptable vehicles so as to provide a composition forproper administration to a patient. Suitable pharmaceutical vehicles aredescribed in the art.

In certain embodiments, a PPAR gamma agonist and an Nrf2 activator maytogether be incorporated into pharmaceutical compositions to beadministered orally. Oral administration of such pharmaceuticalcompositions may result in uptake of the PPAR gamma agonist and the Nrf2activator throughout the intestine and entry into the systemiccirculation. Such oral compositions may be prepared in a manner known inthe pharmaceutical art and comprise a PPAR gamma agonist and an Nrf2activator and at least one pharmaceutically acceptable vehicle. Oralpharmaceutical compositions may include a therapeutically effectiveamount of a PPAR gamma agonist and an Nrf2 activator and a suitableamount of a pharmaceutically acceptable vehicle, so as to provide anappropriate form for administration to a patient.

A PPAR gamma agonist and an Nrf2 activator may together be incorporatedinto pharmaceutical compositions to be administered by any otherappropriate route of administration including intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intracerebral, intravaginal, transdermal,rectal, inhalation, or topical.

In one embodiment of the present invention, a topical formulation isprovided, containing a PPAR agonist, such as a glitazone likepioglitazone or rosiglitazone, and an Nrft2 activator, preferably anNrf2 activator that does not or only rarely causes an allergic skinreaction, such as bardoxolone methyl, CDDO, CDDO-IM, CDDO-MA, TP-225,menadione, vitamin K1, BHA, BHT, tBHQ, tBQ, curcumin, resveratrol,cinnamic aldehyde or oltipraz. The topical formulation is preferablyused in the treatment of psoriasis, acne, rosacea and skin rash such asskin rash caused by EGFR inhibitors like cetuximab, zalutumumab,nimotuzumab, matuzumab, gefitinib, erlotinib, and lapatinib. Theformulations are prepared with customary ingredients and processes knownin the art and/or disclosed herein.

Pharmaceutical compositions comprising a PPAR gamma agonist and an Nrf2activator may be manufactured by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping, or lyophilizing processes. Pharmaceuticalcompositions may be formulated in a conventional manner using one ormore physiologically acceptable carriers, diluents, excipients, orauxiliaries, which facilitate processing of the PPAR gamma agonist andthe Nrf2 activator or crystalline forms thereof and one or morepharmaceutically acceptable vehicles into formulations that can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Pharmaceutical compositions provided by thepresent disclosure may take the form of solutions, suspensions,emulsions, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foradministration to a patient. Pharmaceutical compositions provided by thepresent disclosure may be formulated in a unit dosage form. A unitdosage form refers to a physically discrete unit suitable as a unitarydose for patients undergoing treatment, with each unit containing apredetermined quantity of a PPAR gamma agonist and an Nrf2 activatorcalculated to produce an intended therapeutic effect. A unit dosage formmay be for a single daily dose, for administration 2 times per day, orone of multiple daily doses, e.g., 3 or more times per day. Whenmultiple daily doses are used, a unit dosage form may be the same ordifferent for each dose. One or more dosage forms may comprise a dose,which may be administered to a patient at a single point in time orduring a time interval.

Pharmaceutical compositions comprising a PPAR gamma agonist and an Nrf2activator may be formulated for immediate release or controlled,sustained or delayed release.

In certain embodiments, an oral dosage form provided by the presentdisclosure may be a controlled release dosage form. Controlled deliverytechnologies can improve the absorption of a drug in a particular regionor regions of the gastrointestinal tract. Controlled drug deliverysystems may be designed to deliver a drug in such a way that the druglevel is maintained within a therapeutically effective window andeffective and safe blood levels are maintained for a period as long asthe system continues to deliver the drug with a particular releaseprofile in the gastrointestinal tract. Controlled drug delivery mayproduce substantially constant blood levels of the PPAR gamma agonistand the Nrf2 activator over a period of time as compared to thefluctuations observed with immediate release dosage forms. For some PPARgamma agonists and Nrf2 activators, maintaining a constant blood andtissue concentration throughout the course of therapy is the mostdesirable mode of treatment. Immediate release of the PPAR gamma agonistand the Nrf2 activator may cause blood levels to peak above the levelrequired to elicit a desired response, which may waste the agents andmay cause or exacerbate toxic side effects. Controlled drug delivery canresult in optimal therapy, and not only can reduce the frequency ofdosing, but may also reduce the severity of side effects. Examples ofcontrolled release dosage forms include dissolution controlled systems,diffusion controlled systems, ion exchange resins, osmoticallycontrolled systems, erodable matrix systems, pH independentformulations, gastric retention systems, and the like.

An appropriate oral dosage form for a particular pharmaceuticalcomposition provided by the present disclosure may depend, at least inpart, on the gastrointestinal absorption properties of the PPAR gammaagonist and the Nrf2 activator, the stability of these agents in thegastrointestinal tract, the pharmacokinetics thereof and the intendedtherapeutic profile. An appropriate controlled release oral dosage formmay be selected for a particular PPAR gamma agonist and Nrf2 activator.For example, gastric retention oral dosage forms may be appropriate foragents absorbed primarily from the upper gastrointestinal tract, andsustained release oral dosage forms may be appropriate for agentsabsorbed primarily from the lower gastrointestinal tract.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may be practiced with dosage forms adapted to providesustained release of a PPAR gamma agonist and an Nrf2 activator uponoral administration. Sustained release oral dosage forms may be used torelease the PPAR gamma agonist and/or the Nrf2 activator over aprolonged time period and are useful when it is desired that an agent bedelivered to the lower gastrointestinal tract. Sustained release oraldosage forms include any oral dosage form that maintains therapeuticconcentrations of the agents in a biological fluid such as the plasma,blood, cerebrospinal fluid, or in a tissue or organ for a prolonged timeperiod. Sustained release oral dosage forms include diffusion-controlledsystems such as reservoir devices and matrix devices,dissolution-controlled systems, osmotic systems, and erosion-controlledsystems. Sustained release oral dosage forms and methods of preparingthe same are well-known in the art.

In each of the above dosage forms, the PPAR gamma agonist may beformulated together in admixture or preferably separately from the Nrf2activator. Each of the PPAR gamma agonist and Nrf2 activator maypreferably be contained in separate form within the dosage form, such asan oral dosage form, which is preferably a tablet or capsule. In suchoral dosage form, wherein the PPAR gamma agonist and the Nrf2 activatorare separated, each agent may be formulated with different excipients.The PPAR gamma agonist and the Nrf2 activator may also each be containedin formulations with different release profiles, i.e., with immediate,controlled or delayed release.

The formulations and in particular the solid oral dosage formscontaining a PPAR gamma agonist and/or an Nrf2 activator may contain aconventional additive in the field of pharmaceutical preparation and canbe also produced according to a known method. As the additive, forexample, an excipient, disintegrant, binder, lubricant, coloring agent,pH regulator, surfactant, release-sustaining agent, stabilizer, souragent, flavor, glidant and the like can be mentioned. These additivesare used in an amount conventionally employed in the field ofpharmaceutical preparation.

As the excipient, for example, starches such as corn starch, potatostarch, wheat starch, rice starch, partly pregelatinized starch,pregelatinized starch, porous starch and the like; sugars and sugaralcohols such as lactose, fructose, glucose, D-mannitol, sorbitol andthe like; anhydrous calcium phosphate, crystalline cellulose,precipitated calcium carbonate, calcium silicate and the like can bementioned.

As the disintegrant, for example, carboxymethyl cellulose, calciumcarboxymethyl cellulose, sodium carboxymethyl starch, croscarmellosesodium, crospovidone, low-substituted hydroxypropyl cellulose,hydroxypropyl starch and the like are used. The amount of thedisintegrant to be used is preferably 0.5-25 parts by weight, morepreferably 1-15 parts by weight, per 100 parts by weight of the solidpreparation.

As the binder, for example, crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, gumarabic powder and the like can be mentioned. The amount of the binder tobe used is preferably 0.1-50 parts by weight, more preferably 0.5-40parts by weight, per 100 parts by weight of the solid preparation.

Preferable examples of the lubricant include magnesium stearate, calciumstearate, talc, sucrose esters of fatty acids, sodium stearyl fumarateand the like. As the coloring agent, for example, food colors such asFood Yellow No. 5, Food Red No. 2, Food Blue No. 2 and the like, foodlake colors, ferric oxide and the like can be mentioned. As the pHregulator, citrate, phosphate, carbonate, tartrate, fumarate, acetate,amino acid salt and the like can be mentioned. As the surfactant, sodiumlauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene(30) glycol and the like can be mentioned.

As the release-sustaining agent, for example, cellulose polymers such ashydroxypropyl cellulose, hydroxypropylmethyl cellulose (preferablyhydroxypropylmethyl cellulose 2910, hydroxypropylmethyl cellulose 2208and the like), cellulose acetate (preferably cellulose acetate having anacetyl content of 39.3-40%), cellulose diacetate, cellulose triacetate,cellulose acetate propionate, ethyl cellulose, sodium carboxymethylcellulose, crystalline cellulose sodium carboxymethyl cellulose and thelike; sodium alginate; carboxyvinyl polymer; acrylic acid polymers suchas aminoalkylmethacrylate copolymer RS [Eudragit RS (trademark), RohmPharma] and ethyl acrylate-methyl methacrylate copolymer suspension[Eudragit NE (trademark), Rohm Pharma]; and the like can be mentioned.The release-sustaining agent may contain, for example, flux enhancers(e.g., sodium chloride, potassium chloride, sucrose, sorbitol,D-mannitol, polyethylene glycol (preferably polyethylene glycol 400 andthe like), propylene glycol, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate,cellulose acetate phthalate, polyvinyl alcohol, methacrylic acidpolymer), plasticizers (e.g., triacetin, acetylated monoglyceride, grapeseed oil, olive oil, sesame oil, acetyltributyl citrate, acetyltriethylcitrate, glycerin sorbitol, diethyl oxalate, diethyl maleate, diethylfumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate,dibutyl sebacate, triethyl citrate, tributyl citrate, glyceroltributyrate) and the like. Preferable examples of the release-sustainingagent include: (1) a semipermeable membrane coating containing celluloseacetate (preferably cellulose acetate having an acetyl content of39.3-40%), polyethylene glycol (preferably polyethylene glycol 400 orthe like) and triacetin; (2) a release-sustaining composition containingsodium carboxymethyl cellulose, hydroxypropylmethyl cellulose 2910,hydroxypropylmethyl cellulose 2208 and microcrystalline cellulose; andthe like.

As the stabilizer, for example, tocopherol, tetrasodium edetate,nicotinamide, cyclodextrins and the like can be mentioned. As the souragent, for example, ascorbic acid, citric acid, tartaric acid, malicacid and the like can be mentioned. As the flavor, for example, menthol,peppermint oil, lemon oil, vanillin and the like can be mentioned. Asthe glidant, for example, light anhydrous silicic acid, hydrated silicondioxide and the like can be mentioned. The above-mentioned additives maybe used in a mixture of two or more kinds thereof in an appropriateratio.

Use

An appropriate dose of each PPAR gamma agonist and Nrf2 activator may bedetermined based on several factors, including, for example, the bodyweight and/or condition of the patient being treated, the severity ofthe disease being treated, the incidence and/or severity of sideeffects, the manner of administration, and the judgment of theprescribing physician. Appropriate dose ranges may be determined bymethods known to those skilled in the art.

In one embodiment the invention provides a combination of an Nrf2activator and a PPAR gamma agonist for use in the treatment ofinflammatory and autoimmune diseases.

In another embodiment, the invention provides a PPAR gamma agonist foruse in combination with a fumaric acid mono- and/or diester,characterized in that the PPAR gamma agonist is selective and has nosubstantial activity on PPAR alpha or delta.

A therapeutically effective amount of a combination of a PPAR gammaagonist and an Nrf2 activator may be administered as a treatment orpreventative measure to a patient having a predisposition for and/orhistory of immunological, autoimmune, and/or inflammatory diseasesincluding psoriasis, asthma and chronic obstructive pulmonary diseases,cardiac insufficiency including left ventricular insufficiency,myocardial infarction and angina pectoris, mitochondrial andneurodegenerative diseases such as Parkinson's disease, Alzheimer'sdisease, Huntington's disease, dementia, retinopathia pigmentosa andmitochondrial encephalomyopathy, transplantation rejection, autoimmunediseases including multiple sclerosis, ischemia and reperfusion injury,advanced glycation end-product (AGE)-induced genome and protein damage,inflammatory bowel diseases such as Crohn's disease and ulcerativecolitis, thyroid eye disease-related inflammation, fibrosis, such aslung fibrosis, chronic lymphocytic leukemia, aphthous stomatitis, suchas recurrent aphthous stomatitis, acute lung injury, non-alcoholicsteatohepatitis, acute renal injury and aging-related progressive renalinjury, diabetic cardiomyopathy and nephropathy, chronic kidney disease(CKD), atherosclerosis, hypercholesterolemia, hyperlipidemia, aorticstenosis, and acute kidney injury (AKI) after surgery. The presentinvention can also be used in the prevention of cardiovascular disease,for plaque stabilization, reduction of inflammation, reversal ofendothelial dysfunction, and decreased thrombogenicity and wound healingin diabetes. Moreover, the combination treatment of the presentinvention can be used in the treatment and prevention of atopicdermatitis, dementia, gastritis, fibrosis, insulin resistance, type Iand type II diabetes and Syndrome X.

In a preferred embodiment of the present invention the Nrf2 activator isselected from sulfasalazine2-Hydroxy-5-[4-(2-pyridylsulfamoyl)-phenyldiazenyl]-benzoic acid,5-[4-(2-Pyridylsulfamoyl)-phenylazo]salicylic acid, mesalamine, and5-amino-2-hydroxy-benzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenylester hydrochloride (ATB-429). According to the present invention, theseNrf2 activators are preferably combined with a glitazone, such aspioglitazone or rosiglitazone. More preferably, these combinations arepreferably used for the treatment of IBS and arthritic diseases.

In a preferred embodiment of the present invention a fumaric acid ester,such as dimethyl fumarate, is combined with a glitazone, such aspioglitazone or rosiglitazone, for the treatment of chronic kidneydisease (CKD).

In one embodiment of the present invention, the combination treatment ispreferably used in the prophylaxis or treatment of polycystic ovarysyndrome (PCOS). It can also be found that compounds that are both PPARgamma agonists and Nrf2 activators show suitable effects asmonotherapeutic agents. Preferred compounds which can be used in theprophylaxis and treatment of PCOS as a single active ingredient in adosage form such as a tablet are bardoxolone methyl, CDDO, CDDO-IM,CDDO-MA and TP-225. Thus, another object of the present invention is theuse of bardoxolone methyl, CDDO, CDDO-IM, CDDO-MA or TP-225 in theprophylaxis and treatment of PCOS and a method of treating PCOS byadministration of a pharmacologically effective amount of bardoxolonemethyl, CDDO, CDDO-IM, CDDO-MA, TBE-31 or TP-225 or another Nrf2activator to a patient in need thereof. In many instances, themonotherapy with the aforementioned Nrf2 activators can be furtherimproved with co-administration of a PPAR agonist, such as a glitazonelike pioglitazone or rosiglitazone.

NF-κB mediated and/or other diseases are described in the following.

According to another embodiment of the invention, the administration orco-administration of a combination of a PPAR gamma agonist and an Nrf2activator is effective for treating a member of the group of diseasesconsisting of a neurological disorder, or an ophthalmological disorderin a mammal, including, without limitation, a human. According toanother embodiment the neurological disorder, ophthalmological disorder,or combination thereof results from at least one member of the groupconsisting of trauma, ischemia, and hypoxia. According to anotherembodiment the neurological disorder, ophthalmological disorder, orcombination thereof is selected from the group consisting of painfulneuropathy, neuropathic pain, diabetic neuropathy, drug dependence, drugaddiction, drug withdrawal, nicotine withdrawal, opiate tolerance,opiate withdrawal, depression, anxiety, a movement disorder, tardivedyskinesia, a cerebral infection that disrupts the blood-brain barrier,meningitis, meningoencephalitis, stroke, hypoglycemia, cardiac arrest,spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest,hypoglycemic neuronal damage, glaucoma, retinal ischemia, ischemic opticneuropathy, macular degeneration, multiple sclerosis, sequelae ofhyperhomocystinemia, convulsion, pain, schizophrenia, muscle spasm,migraine headache, urinary incontinence, emesis, brain edema, tardivedyskinesia, AIDS-induced dementia, ocular damage, retinopathy, acognitive disorder, and a neuronal injury associated with HIV infection.According to another embodiment the neurological disorder,ophthalmological disorder, or combination thereof is selected from thegroup consisting of epilepsy, Alzheimer's disease, vascular(multi-infarct) dementia, Huntington's disease, Parkinsonism, multiplesclerosis, amyotrophic lateral sclerosis, and minimal cognitiveimpairment (MCI).

Psoriasis is characterized by hyperkeratosis and thickening of theepidermis as well as by increased vascularity and infiltration ofinflammatory cells in the dermis. Psoriasis vulgaris manifests assilvery, scaly, erythematous plaques, typically on the scalp, elbows,knees, and buttocks. Guttate psoriasis occurs as teardrop-size lesions.Fumaric acid esters are recognized for the treatment of psoriasis anddimethyl fumarate is approved for the systemic treatment of psoriasis inGermany (Mrowietz and Asadullah, Trends Mol Med 2005, 11(1), 43-48; andMrowietz et al, Br J Dermatology 1999, 141, 424-429). Efficacy fortreating psoriasis can be determined using animal models and in clinicaltrials. Contrary to fumaric acid esters, it has been found that PPARgamma agonists are not advantageous in the treatment of psoriasis(Placebo response in two long-term randomized psoriasis studies that arenegative for rosiglitazone. Am J Clin Dermatol. 2007; 8(2):93-102).Contrary to this result, it can be found that PPAR gamma agonistsprovide therapeutic benefit in a combined treatment of psoriasisaccording to the present invention.

Inflammatory arthritis includes diseases such as rheumatoid arthritis,juvenile rheumatoid arthritis (juvenile idiopathic arthritis), psoriaticarthritis, and ankylosing spondylitis which produce joint inflammation.The pathogenesis of immune-mediated inflammatory diseases includinginflammatory arthritis is believed to involve TNF and NK-κB signalingpathways (Tracey et al., Pharmacology & Therapeutics 2008, 117,244-279). Dimethyl fumarate has been shown to inhibit TNF andinflammatory diseases including inflammatory arthritis which arebelieved to involve TNF and NK-κB signaling, and may therefore be usefulin treating inflammatory arthritis (Lowewe et al., J Immunology 2002,168, 4781-4787).

Preferably the inventive method of treatment and combinations can beused in the prophylaxis and treatment of neurodegenerative diseases,such as multiple sclerosis, clinically isolated syndrome (CIS) leadingto multiple sclerosis, Parkinson's disease, Alzheimer's disease,Huntington's disease, dementia, mitochondrial encephalomyopathy andamyotrophic lateral sclerosis (ALS).

Multiple sclerosis (MS) is an inflammatory autoimmune disease of thecentral nervous system caused by an autoimmune attack against theisolating axonal myelin sheets of the central nervous system.Demyelination leads to the breakdown of conduction and to severe diseasewith destruction of local axons and irreversible neuronal cell death.The symptoms of MS are highly varied with each individual patientexhibiting a particular pattern of motor, sensible, and sensorydisturbances. MS is typified pathologically by multiple inflammatoryfoci, plaques of demyelination, gliosis, and axonal pathology within thebrain and spinal cord, all of which contribute to the clinicalmanifestations of neurological disability (see, e.g., Wingerchuk, LabInvest 2001, 81, 263-281; and Virley, NeuroRx 2005, 2(4), 638-649).Although the causal events that precipitate MS are not fully understood,evidence implicates an autoimmune etiology together with environmentalfactors, as well as specific genetic predispositions. Functionalimpairment, disability, and handicap are expressed as paralysis, sensoryand octintive disturbances, spasticity, tremor, lack of coordination,and visual impairment, which impact the quality of life of theindividual. The clinical course of MS can vary from individual toindividual, but invariably the disease can be categorized in threeforms: relapsing-remitting, secondary progressive, and primaryprogressive.

Studies support the efficacy of fumaric acid esters for treating MS andthey have undergone phase II clinical testing (Schimrigk et al., Eur JNeurology 2006, 13, 604-610; and Wakkee and Thio, Current OpinionInvestigational Drugs 2007, 8(11), 955-962). Assessment of MS treatmentefficacy in clinical trials can be accomplished using tools such as theExpanded Disability Status Scale and the MS Functional Composite as wellas magnetic resonance imaging of lesion load, biomarkers, andself-reported quality of life. Animal models of MS shown to be useful toidentify and validate potential therapeutics include experimentalautoimmune/allergic encephalomyelitis (EAE) rodent models that simulatethe clinical and pathological manifestations of MS and nonhuman primateEAE models.

Inflammatory bowel disease (IBD) is a group of inflammatory conditionsof the large intestine and in some cases, the small intestine thatincludes Crohn's disease and ulcerative colitis. Crohn's disease, whichis characterized by areas of inflammation with areas of normal lining inbetween, can affect any part of the gastrointestinal tract from themouth to the anus. The main gastrointestinal symptoms are abdominalpain, diarrhea, constipation, vomiting, weight loss, and/or weight gain.Crohn's disease can also cause skin rashes, arthritis, and inflammationof the eye. Ulcerative colitis is characterized by ulcers or open soresin the large intestine or colon. The main symptom of ulcerative colitisis typically constant diarrhea with mixed blood of gradual onset. Othertypes of intestinal bowel disease include collagenous colitis,lymphocytic colitis, ischemic colitis, diversion colitis, Behcet'scolitis, and indeterminate colitis.

Asthma is a reversible airway obstruction in which the airwayoccasionally constricts, becomes inflamed, and is lined with anexcessive amount of mucus. Symptoms of asthma include dyspnea, wheezing,chest tightness, and cough. Asthma episodes may be induced by airborneallergens, food allergies, medications, inhaled irritants, physicalexercise, respiratory infection, psychological stress, hormonal changes,cold weather, or other factors.

As shown in animal studies (Joshi et al., US 2007/0027076), fumaric acidesters may be useful in treating pulmonary diseases such as asthma andchronic obstructive pulmonary disorder.

Chronic obstructive pulmonary disease (COPD), also known as chronicobstructive airway disease, is a group of diseases characterized by thepathological limitation of airflow in the airway that is not fullyreversible, and includes conditions such as chronic bronchitis andemphysema, as well as other lung disorders such as asbestosis,pneumoconiosis, and pulmonary neoplasms (see, e.g., Barnes,Pharmacological Reviews 2004, 56(4), 515-548). The airflow limitation isusually progressive and associated with an abnormal inflammatoryresponse of the lungs to noxious particles and gases. COPD ischaracterized by a shortness of breath that lasts for months or years,possibly accompanied by wheezing, and a persistent cough with sputumproduction. COPD is most often caused by tobacco smoking, although itcan also be caused by other airborne irritants such as coal dust,asbestos, urban pollution, or solvents. COPD encompasses chronicobstructive bronchiolitis with fibrosis and obstruction of smallairways, and emphysema with enlargement of airspaces and destruction oflung parenchyma, loss of lung elasticity, and closure of small airways.

Neurodegenerative diseases such as Parkinson's disease, Alzheimer'sdisease, Huntington's disease and amyotrophic lateral sclerosis arecharacterized by progressive dysfunction and neuronal death.

Parkinson's disease is a slowly progressive degenerative disorder of thenervous system characterized by tremor when muscles are at rest (restingtremor), slowness of voluntary movements, and increased muscle tone(rigidity). In Parkinson's disease, nerve cells in the basal ganglia,e.g., substantia nigra, degenerate, and thereby reduce the production ofdopamine and the number of connections between nerve cells in the basalganglia. As a result, the basal ganglia are unable to smooth musclemovements and coordinate changes in posture as normal, leading totremor, incoordination, and slowed, reduced movement (bradykinesia)(Blandini, et al., Mol. Neurobiol. 1996, 12, 73-94).

Alzheimer's disease is a progressive loss of mental functioncharacterized by degeneration of brain tissue, including loss of nervecells and the development of senile plaques and neurofibrillary tangles.In Alzheimer's disease, parts of the brain degenerate, destroying nervecells and reducing the responsiveness of the maintaining neurons toneurotransmitters. Abnormalities in brain tissue consist of senile orneuritic plaques, i.e., clumps of dead nerve cells containing anabnormal, insoluble protein called amyloid, and neurofibrillary tangles,twisted strands of insoluble proteins in the nerve cell.

Huntington's disease is an autosomal dominant neurodegenerative disorderin which specific cell death occurs in the neostriatum and cortex(Martin, N Engl J Med 1999, 340, 1970-80). Onset usually occurs duringthe fourth or fifth decade of life, with a mean survival at age of onsetof 14 to 20 years. Huntington's disease is universally fatal, and thereis no effective treatment. Symptoms include a characteristic movementdisorder (Huntington's chorea), cognitive dysfunction, and psychiatricsymptoms. The disease is caused by a mutation encoding an abnormalexpansion of CAG-encoded polyglutamine repeats in the proteinhuntingtin.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerativedisorder characterized by the progressive and specific loss of motorneurons in the brain, brain stem, and spinal cord (Rowland andSchneider, N Engl J Med 2001, 344, 1688-1700). ALS begins with weakness,often in the hands and less frequently in the feet, that generallyprogresses up an arm or leg. Over time, weakness increases andspasticity develops, characterized by muscle twitching and tightening,followed by muscle spasms and possibly tremors. The average age of onsetis 55 years, and the average life expectancy after the clinical onset is4 years. The only recognized treatment for ALS is riluzole, which canextend survival by only about three months.

Myasthenia gravis (MG) is a classic autoimmune disease affectingneuromuscular junctions of striated muscle. Immunization of differentanimal species with acetylcholine receptor (AChR) and complete Freund'sadjuvant (CFA) results in an animal model of MG named experimentalautoimmune myasthenia gravis (EAMG).

Alopecia areata is a common disease, but for ethical reasons it seemsdifficult to perform large-scale studies to elucidate the pathogenesisand to develop new therapeutic approaches in man. It is thereforehelpful to develop appropriate animal models. The Dundee experimentalbald rat (DEBR) and the C3H/HeJ mouse are well-established animal modelsfor alopecia areata and can be used for the study of genetic aspects,pathogenesis and therapy of the disease (J Dtsch Dermatol Ges. 2004April; 2(4):260-73).

A mouse model for diabetic nephropathy can be utilized according toKidney International 77, 749-750 (May 2010), in order to prove theeffect of the combination according to the present invention.

Thus, diseases and conditions for which treatment with the combinationof a PPAR gamma agonist and an Nrf2 activator can be useful includerheumatica, granuloma annulare, lupus, autoimmune carditis, eczema,sarcoidosis, and autoimmune diseases including acute disseminatedencephalomyelitis, Addison's disease, alopecia areata, ankylosingspondylitis, antiphospholipid antibody syndrome, autoimmune hemolyticanemia, autoimmune hepatitis, autoimmune inner ear disease, bullouspemphigoid, Behcet's disease, celiac disease, Chagas disease, chronicobstructive pulmonary disease, Crohn's disease, dermatomyositis,diabetes mellitus type I, endometriosis, Goodpasture's syndrome, Graves'disease, Guillain-Barré syndrome, Hashimoto's disease, hidradenitissuppurativea, Kawasaki disease, IgA neuropathy, idiopathicthrombocytopenic purpura, interstitial cystitis, lupus erythematosus,mixed connective tissue disease, morphea, multiple sclerosis, myastheniagravis, narcolepsy, neuromyotonia, pemphigus vulgaris, perniciousanaemia, psoriasis, psoriatic arthritis, polymyositis, primary biliarycirrhosis, rheumatoid arthritis, schizophrenia, scleroderma, Sjögren'ssyndrome, stiff person syndrome, temporal arteritis, ulcerative colitis,vasculitis, vitiligo, and Wegener's granulomatosis.

Administration

The combination of an Nrf2 activator and a PPAR gamma agonist andpharmaceutical compositions thereof may be administered orally or by anyother appropriate route, for example, by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings (e.g., oral,rectal, and intestinal mucosa, etc.). Other suitable routes ofadministration include, but are not limited to intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intracerebral, intravaginal, transdermal,rectal, inhalation, or topical.

Administration may be systemic or local. Various delivery systems areknown (e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc.) that may be used to administer a compound and/orpharmaceutical composition.

For systemic administration, a therapeutically effective dose may beestimated initially from in vitro assays. For example, a dose may beformulated in animal models to achieve a beneficial circulatingcomposition concentration range. Initial doses may also be estimatedfrom in vivo data, e.g., animal models, using techniques that are knownin the art. Such information may be used to more accurately determineuseful doses in humans. One having ordinary skill in the art mayoptimize administration to humans based on animal data.

The embodiment “PPAR gamma agonist for use in combination with a fumaricacid mono- and/or diester in the treatment of an autoimmune and/orinflammatory disease” relates to a method of use of at least one PPARgamma agonist in combination with a fumaric acid mono- and/or diester inthe treatment of an autoimmune and/or inflammatory disease.

Preferred embodiments of the invention are described below.

1. PPAR gamma agonist for use in combination with a fumaric acid mono-and/or diester in the treatment of an autoimmune and/or inflammatorydisease.

2. PPAR gamma agonist, such as rosiglitazone, for use in combinationwith a fumaric acid mono- and/or diester according to embodiment 1,characterized in that the autoimmune and/or inflammatory disease ispsoriasis.

3. PPAR gamma agonist for use in combination with a fumaric acid mono-and/or diester according to one or more of the foregoing embodimentsand/or embodiment 1, characterized in that the autoimmune and/orinflammatory disease is selected from the group of psoriatic arthritis,multiple sclerosis, inflammatory bowel disease (IBS), ulcerativecolitis, Crohn's disease, hepatitis, effluvium, alopecia areata,cicatricial alopecia, diabetic nephrophathy, CKD and myasthenia gravis.

4. PPAR gamma agonist for use in combination with a fumaric acid mono-and/or diester, according to the aforementioned embodiments,characterized in that the PPAR gamma agonist is selected from the groupof rosiglitazone, pioglitazone, troglitazone and ciglitazone.

5. PPAR gamma agonist for use in combination with a fumaric acid mono-and/or diester, according to the aforementioned embodiments,characterized in that the fumaric acid mono- and/or diester is selectedfrom the group of monomethyl hydrogen fumarate, dimethyl fumarate,monoethyl hydrogen fumarate and diethyl fumarate.

6. A pharmaceutical composition comprising a PPAR gamma agonist and afumaric acid mono- and/or diester and optionally one or more excipients.

7. A pharmaceutical composition comprising rosiglitazone, pioglitazone,troglitazone or ciglitazone and a fumaric acid mono- and/or diester andoptionally one or more excipients.

8. A pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiments 6 or 7, characterized in thatthe fumaric acid mono- and/or diester is selected from the group ofmonomethyl hydrogen fumarate, dimethyl fumarate, monoethyl hydrogenfumarate, and diethyl fumarate.

9. A solid oral dosage form comprising a PPAR gamma agonist and afumaric acid mono- and/or diester.

10. A solid oral dosage form comprising rosiglitazone, pioglitazone,troglitazone or ciglitazone as a PPAR gamma agonist and a fumaric acidmono- and/or diester.

11. A solid oral dosage form according to one or more of the foregoingembodiments and/or embodiments 9 or 10, characterized in that thefumaric acid mono- and/or diester is selected from the group ofmonomethyl hydrogen fumarate, dimethyl fumarate, monoethyl hydrogenfumarate, and diethyl fumarate.

12. A solid oral dosage form according to one or more of the foregoingembodiments and/or embodiments 9 to 10, characterized in that the PPARgamma agonist and the fumaric acid mono- and/or diester are eachcontained in the dosage form in a separate composition optionallycontaining one or more excipients.

13. Kit of parts comprising a) a PPAR gamma agonist, b) a fumaric acidmono- and/or diester and optionally c) instructions for a dosingregimen.

14. Kit of parts comprising a) rosiglitazone, pioglitazone, troglitazoneor ciglitazone, b) a fumaric acid mono- and/or diester and optionally c)instructions for a dosing regimen.

15. Kit of parts according to one or more of the foregoing embodimentsand/or embodiments 13 or 14, characterized in that the fumaric acidmono- and/or diester is selected from the group of monomethyl hydrogenfumarate, dimethyl fumarate, monoethyl hydrogen fumarate, and diethylfumarate.

16. PPAR gamma agonist for use in combination with an Nrf2 activatorselected from the group of monoalkyl hydrogen fumarate, dialkyl fumarateand bardoxolone alkyl in the treatment of multiple sclerosis.

17. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to the foregoing embodiments, characterized in that multiplesclerosis includes relapsing-remitting (RR), secondary progressive (SP),primary progressive (PP) and progressive relapsing (PR) multiplesclerosis and the first demyelinating event suggestive of MS orclinically isolated syndrome (CIS).

18. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to the foregoing embodiments, characterized in that the PPARgamma agonist is a glitazone.

19. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to the foregoing embodiments, characterized in that the PPARgamma agonist is a glitazone selected from the group of pioglitazone androsiglitazone.

20. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to the foregoing embodiments, characterized in that Nrf2activator is selected from the group of monomethyl hydrogen fumarate,dimethyl fumarate and bardoxolone methyl.

21. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to the foregoing embodiments, characterized in that ratiosbetween rosiglitazone and dimethyl fumarate are selected from 1/20 to1/400 (w/w, rosiglitazone/dimethyl fumarate).

22. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to the foregoing embodiments, characterized in that ratiosbetween pioglitazone and dimethyl fumarate are selected from 1/3 to 1/60(w/w, pioglitazone/dimethyl fumarate).

23. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to the foregoing embodiments, characterized in that ratiosbetween rosiglitazone and bardoxolone methyl are selected from 1/1 to1/100 (w/w, rosiglitazone/bardoxolone methyl).

24. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to the foregoing embodiments, characterized in thatbardoxolone methyl is employed in its amorphous form and ratios betweenrosiglitazone and bardoxolone methyl are from 1/1 to 1/20 (w/w,rosiglitazone/bardoxolone methyl).

25. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to the foregoing embodiments, characterized in that ratiosbetween pioglitazone and bardoxolone methyl are selected from 1/0.1 to1/20 (w/w, pioglitazone/bardoxolone methyl).

26. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to the foregoing embodiments, characterized in thatbardoxolone methyl is employed in its amorphous form and ratios betweenpioglitazone and bardoxolone methyl are from 1/0.1 to 1/3 (w/w,pioglitazone/bardoxolone methyl).

27. A pharmaceutical composition comprising a PPAR gamma agonist and anNrf2 activator selected from the group of monoalkyl hydrogen fumarate,dialkyl fumarate and bardoxolone alkyl and optionally one or moreexcipients.

28. A pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiment 27, characterized in that thePPAR gamma agonist is a glitazone.

29. A pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiment 28, characterized in that theglitazone is selected from the group of pioglitazone and rosiglitazone.

30. A pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiments 28 to 30, characterized in thatthe Nrf2 activator is selected from the group of monomethyl hydrogenfumarate, dimethyl fumarate and bardoxolone methyl.

31. A pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiments 28 to 30, characterized in thatratios between rosiglitazone and dimethyl fumarate are selected from1/20 to 1/400 (w/w, rosiglitazone/dimethyl fumarate).

32. A pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiments 28 to 30, characterized in thatratios between pioglitazone and dimethyl fumarate are selected from 1/3to 1/60 (w/w, pioglitazone/dimethyl fumarate).

33. A pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiments 28 to 30, characterized in thatratios between rosiglitazone and bardoxolone methyl are selected from1/1 to 1/100 (w/w, rosiglitazone/bardoxolone methyl).

34. A pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiments 28 to 30, characterized in thatbardoxolone methyl is employed in its amorphous form and ratios betweenrosiglitazone and bardoxolone methyl are from 1/1 to 1/20 (w/w,rosiglitazone/bardoxolone methyl).

35. A pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiments 28 to 30, characterized in thatratios between pioglitazone and bardoxolone methyl are selected from1/0.1 to 1/20 (w/w, pioglitazone/bardoxolone methyl).

36. A pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiments 28 to 30, characterized inbardoxolone methyl is employed in its amorphous form and ratios betweenpioglitazone and bardoxolone methyl are from 1/0.1 to 1/3 (w/w,pioglitazone/bardoxolone methyl).

37. A solid oral dosage form comprising the pharmaceutical compositionaccording to one or more of the foregoing embodiments and/or embodiments27 to 36.

38. A solid oral dosage form comprising a PPAR gamma agonist and an Nrf2activator selected from the group of monoalkyl hydrogen fumarate,dialkyl fumarate and bardoxolone alkyl and optionally one or moreexcipients, wherein the PPAR gamma agonist and the Nrf2 activator areeach contained in a separate pharmaceutical formulation.

39. A solid oral dosage form according to one or more of the foregoingembodiments and/or embodiment 38, wherein the PPAR gamma agonist is aglitazone and the Nrf2 activator is selected from the group ofmonomethyl hydrogen fumarate, dimethyl fumarate and bardoxolone methyl.

40. A solid oral dosage form according to the aforementionedembodiments, wherein the Nrf2 activator is bardoxolone methyl containedin its amorphous form.

41. A solid oral dosage form according to the aforementionedembodiments, wherein the Nrf2 activator is bardoxolone methyl containedin an amorphous dispersion formulation.

42. A solid oral dosage form according to the aforementionedembodiments, wherein the Nrf2 activator is bardoxolone methyl containedin an amorphous dispersion formulation obtained by spray drying orfreeze drying.

43. A solid oral dosage form according to the aforementionedembodiments, wherein the Nrf2 activator is bardoxolone methyl containedin an amorphous dispersion formulation with methacrylic acid copolymerType C, USP.

44. A solid oral dosage form according to the aforementionedembodiments, wherein the Nrf2 activator is bardoxolone methyl containedin an amorphous dispersion formulation with methacrylic acid copolymerType C, USP in a weight ratio of 4/6.

45. A solid oral dosage form according to the aforementionedembodiments, wherein the Nrf2 activator is bardoxolone methyl containedin an amorphous dispersion formulation comprising at least onehydrophilic binder.

46. A solid oral dosage form according to the aforementionedembodiments, wherein the hydrophilic binder is employed in an amount ofbetween about 1 and about 40% (weight % of the total pharmaceuticalcomposition used for the dosage form), preferably between about 2 andabout 20%, more preferably between about 4 and about 10%, even morepreferably between about 5 and about 7.5% and most preferred betweenabout 7 and 7.5%, such as about 7%.

47. A solid oral dosage form according to the aforementionedembodiments, wherein the hydrophilic binder ishydroxypropylmethylcellulose.

48. A solid oral dosage form according to the aforementionedembodiments, wherein the Nrf2 activator is bardoxolone methyl containedin an amorphous dispersion formulation and wherein the dosage form alsocontains a surface active agent, such as sodium lauryl sulfate,preferably in an amount of about 3% of the total weight of the dosageform.

49. Kit of parts comprising a) a PPAR gamma agonist, b) an Nrf2activator selected from the group of monoalkyl hydrogen fumarate,dialkyl fumarate and bardoxolone alkyl and optionally c) instructionsfor a dosing regimen.

50. Kit of parts comprising a) a PPAR agonist, b) an Nrf2 activatorselected from the group of monoalkyl hydrogen fumarate, dialkyl fumarateand bardoxolone alkyl and optionally c) instructions for a dosingregimen.

51. Kit of parts according to the foregoing embodiments, characterizedin that the PPAR gamma agonist is rosiglitazone or pioglitazone.

52. Kit of parts according to the foregoing embodiments, characterizedin that the Nrf2 activator is dimethyl fumarate or bardoxolone methyl.

53. PPAR gamma agonist for use in combination with an Nrf2 activator forthe treatment of multiple sclerosis according to the foregoingembodiments, wherein said PPAR agonist is administered to a patientsimultaneously with or up to 2 days before or after an Nrf2 activator,such as those selected from the group of monoalkyl hydrogen fumarate,dialkyl fumarate and bardoxolone alkyl, is administered to said patient.

54. PPAR gamma agonist for use in combination with an Nrf2 activator forthe treatment of multiple sclerosis according to the foregoingembodiments, wherein said PPAR agonist is administered once or twicedaily.

55. PPAR gamma agonist for use in combination with an Nrf2 activator forthe treatment of multiple sclerosis according to the foregoingembodiments, wherein said Nrf2 activator is administered once or twicedaily.

56. PPAR gamma agonist for use in combination with an Nrf2 activator inthe treatment of autoimmune and/or inflammatory diseases other thanpsoriasis.

57. PPAR gamma agonist, preferably other than pioglitazone, for use, incombination with an Nrf2 activator belonging to a different chemicalclass, in the treatment of autoimmune and/or inflammatory diseases, suchas multiple sclerosis, psoriasis or chronic kidney disease.

58. PPAR gamma agonist, preferably other than pioglitazone, for useaccording to the aforementioned embodiments, wherein the Nrf2 activatorhas no significant PPAR gamma agonistic effect.

59. PPAR gamma agonist, preferably other than pioglitazone, having nosignificant activating effect on Nrf2, for use, in combination with anNrf2 activator having no significant PPAR gamma agonistic effect, in thetreatment of autoimmune and/or inflammatory diseases, such as multiplesclerosis, psoriasis or chronic kidney disease.

60. PPAR gamma agonist, preferably other than pioglitazone, for use, incombination with an Nrf2 activator belonging to a different chemicalclass, wherein the Nrf2 activator is other than bardoxolone methyl andits derivatives, in the treatment of autoimmune and/or inflammatorydiseases, such as multiple sclerosis, psoriasis or chronic kidneydisease.

61. Composition comprising a PPAR gamma agonist and an Nrf2 activatorbelonging to a different chemical class, for use in the treatment ofautoimmune and/or inflammatory diseases, such as multiple sclerosis,psoriasis or chronic kidney disease.

62. Composition according to the aforementioned embodiment, comprising aPPAR gamma agonist having no significant activating effect on Nrf2 andan Nrf2 activator having no significant PPAR gamma agonistic effect, foruse in the treatment of autoimmune and/or inflammatory diseases, such asmultiple sclerosis, psoriasis or chronic kidney disease.

63. Composition comprising a PPAR gamma agonist, such as pioglitazone,and an Nrf2 activator.

64. Composition comprising a PPAR gamma agonist, such as pioglitazone,and an Nrf2 activator having no significant PPAR gamma agonistic effect.

65. Composition comprising pioglitazone and an Nrf2 activator having nosignificant PPAR gamma agonistic effect, for use in the treatment ofpsoriasis and other autoimmune and/or inflammatory diseases, such asmultiple sclerosis, psoriasis or chronic kidney disease.

66. PPAR gamma agonist for use, in combination with an Nrf2 activatorhaving no significant PPAR gamma agonistic effect, in the treatment ofmultiple sclerosis.

67. PPAR gamma agonist for use, in combination with an Nrf2 activatorother than bardoxolone methyl, in the treatment of chronic kidneydisease (CKD) or multiple sclerosis.

68. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to the foregoing embodiments, characterized in that multiplesclerosis includes relapsing-remitting (RR), secondary progressive (SP),primary progressive (PP) and progressive relapsing (PR) multiplesclerosis and the first demyelinating event suggestive of MS orclinically isolated syndrome (CIS).

69. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to the foregoing embodiments, characterized in that the PPARgamma agonist is a glitazone. 70. PPAR gamma agonist for use incombination with an Nrf2 activator according to any of the foregoingembodiments, characterized in that the PPAR gamma agonist is a glitazoneselected from the group of pioglitazone and rosiglitazone.

71. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to any of the foregoing embodiments, characterized in that theNrf2 activator is selected from the chemical compounds belonging to thegroup of Michael reaction acceptors, phenols, diphenols, chalcones,isothiocyanates, thiocarbamates, quinones, naphthoquinones and1,2-dithiole-3-thiones, wherein one or more, preferably 1, 2, 3, 4, 5, 6or 7, H-atoms may be substituted by linear or branched alkyl andperfluoroalkyl such as methyl, ethyl, trifluoromethyl, halogen such asBr, Cl, F or I, hydroxy, alkoxy and perfluoroalkoxy such as methoxy,ethoxy, trifluoromethoxy, cyano and nitro, which chemical compounds haveno more than one or two 5- or 6-membered carbocyclic rings or 5- or6-membered heterocyclic rings having 1, 2 or 3 N-, O- or S-atoms as ringatoms, which rings may be fused to each other, or preferably no or onlyone carbocyclic or heterocyclic ring. Compositions containing these Nrf2activators are preferred.

Preferred Nrf2 activators for use in combinations according to theinvention, and particularly according to embodiment 71 above, arechemical compounds containing less than 35, preferably less than 30,more preferably less than 25, most preferably less than 20, even lessthan 15 or less than 10 carbon atoms and/or having a molecular weight ofless than 400, preferably less than 300, most preferably less than 200g/mol or less than 170 g/mol and/or having no significant PPAR gammaagonistic activity. Compositions containing these Nrf2 activators arepreferred.

72. PPAR gamma agonist for use in combination with an Nrf2 activator andcompositions according to any of the foregoing embodiments,characterized in that the Nrf2 activator is selected from2-naphthoquinone, cinnamic aldehyde, caffeic acid and its esters,curcumin, resveratrol, artesunate, tert-butylhydroquinone, vitamins K1,K2 and K3 and the respective quinone or hydroquinone forms of theaforementioned quinone and hydroquinone derivatives, fumaric acidesters, i.e., fumaric acid mono- and/or diester preferably selected fromthe group of monoalkyl hydrogen fumarate and dialkyl fumarate, such asmonomethyl hydrogen fumarate, dimethyl fumarate, monoethyl hydrogenfumarate, and diethyl fumarate, isothiocyanate such as sulforaphane,1,2-dithiole-3-thione such as oltipraz,3,5-di-tert-butyl-4-hydroxytoluene, 3-hydroxycoumarin, 4-hydroxynonenal,4-oxononenal, malondialdehyde, (E)-2-hexenal, capsaicin, allicin,allylisothiocyanate, 6-methylthiohexyl isothiocyanate,7-methylthioheptyl isothiocyanate, sulforaphane, 8-methylthiooctylisothiocyanate, 8-iso prostaglandin A2, alkyl pyruvate, such as methyland ethyl pyruvate, diethyl or dimethyl oxalopropionate,2-acetamidoacrylate, and methyl or ethyl-2-acetamidoacrylate, and apharmacologically active stereoisomer or derivative of theaforementioned agents.

73. PPAR gamma agonist for use in combination with an Nrf2 activator andcompositions according to any the foregoing embodiments, characterizedin that the nrf2 activator is selected from monomethyl hydrogenfumarate, dimethyl fumarate, oltipraz, 1,2-naphthoquinone,tert-butylhydroquinone, methyl or ethyl pyruvate,3,5-di-tert-butyl-4-hydroxytoluene, diethyl and dimethyloxalopropionate.

74. Kit of parts comprising: a) a PPAR gamma agonist other thanpioglitazone, b) an Nrf2 activator selected from the group of monoalkylhydrogen fumarate, dialkyl fumarate and bardoxolone alkyl and optionallyc) instructions for a dosing regimen.

75. Kit of parts comprising: a) a PPAR gamma agonist having nosignificant activating effect on Nrf2, b) an Nrf2 activator selectedfrom the group of monoalkyl hydrogen fumarate, dialkyl fumarate andbardoxolone and optionally c) instructions for a dosing regimen.

76. Kit of parts comprising: a) a PPAR gamma agonist having nosignificant activating effect on Nrf2, b) an Nrf2 activator having nosignificant PPAR gamma agonistic effect and optionally c) instructionsfor a dosing regimen.

77. Kit of parts comprising: a) a PPAR gamma agonist having nosignificant activating effect on Nrf2, b) an Nrf2 activator selectedfrom the chemical compounds belonging to the group of Michael reactionacceptors, phenols, diphenols, chalcones, isothiocyanates,thiocarbamates, quinones, naphthoquinones and 1,2-dithiole-3-thiones,wherein one or more, preferably 1, 2, 3, 4, 5, 6 or 7, H-atoms may besubstituted by linear or branched alkyl and perfluoroalkyl such asmethyl, ethyl, trifluoromethyl, halogen such as Br, Cl, F or I, hydroxy,alkoxy or perfluoroalkoxy such as methoxy, ethoxy, trifluoromethoxy,cyano and nitro, which chemical compounds have no more than one or two5- or 6-membered carbocyclic rings or 5- or 6-membered heterocyclicrings having 1, 2 or 3 N-, O- or S-atoms as ring atoms, which rings maybe fused to each other, or preferably no or only one carbocyclic orheterocyclic ring and optionally c) instructions for a dosing regimen.

78. Composition comprising: a) a PPAR gamma agonist, preferably otherthan pioglitazone and b) an Nrf2 activator selected from the group ofmonoalkyl hydrogen fumarate, dialkyl fumarate and bardoxolone alkyl.

79. Composition comprising: a) a PPAR gamma agonist having nosignificant activating effect on Nrf2 and b) an Nrf2 activator selectedfrom the group of monoalkyl hydrogen fumarate, dialkyl fumarate andbardoxolone.

80. Composition comprising: a) a PPAR gamma agonist having nosignificant activating effect on Nrf2 and b) an Nrf2 activator having nosignificant PPAR gamma agonistic effect.

81. Composition comprising: a) a PPAR gamma agonist having nosignificant activating effect on Nrf2 and b) an Nrf2 activator selectedfrom the chemical compounds belonging to the group of Michael reactionacceptors, phenols, diphenols, chalcones, isothiocyanates,thiocarbamates, quinones, naphthoquinones and 1,2-dithiole-3-thiones,wherein one or more, preferably 1, 2, 3, 4, 5, 6 or 7, H-atoms may besubstituted by linear or branched alkyl and perfluoroalkyl such asmethyl, ethyl, trifluoromethyl, halogen such as Br, Cl, F or I, hydroxy,alkoxy and perfluoroalkoxy such as methoxy, ethoxy, trifluoromethoxy,cyano and nitro, which chemical compounds have no more than one or two5- or 6-membered carbocyclic rings or 5- or 6-membered heterocyclicrings having 1, 2 or 3 N-, O- or S-atoms as ring atoms, which rings maybe fused to each other, or preferably no or only one carbocyclic orheterocyclic ring.

82. Method of treating or preventing cancer, preferably hematologicalcancer, such as leukemia, such as acute myeloid leukaemia (AML),comprising administration of a PPAR gamma agonist and an Nrf2 activatorto a patient in need thereof, wherein said Nrf2 activator is capable ofprovoking or inducing a stimulated and/or increased nucleartranslocation of Nrf2 protein and is:

a) selected from the group of Michael reaction acceptors, phenols,diphenols, chalcones, isothiocyanates, thiocarbamates, quinones,naphthoquinones and 1,2-dithiole-3-thiones; and

b) contains less than 35 carbon atoms; and/or

c) has a molecular weight of less than 600 g/mol; and/or

d) contains no or not more than one or two fused or monocyclic 5- or6-membered carbocyclic or heterocyclic rings having 1, 2 or 3 ring atomsselected from N, O or S.

In one embodiment of the foregoing method, the Nrf2 activator ispreferably other than arsenic trioxide. Preferably, the Nrf2 activatoris dimethyl fumarate, monomethyl hydrogen fumarate or bardoloxolonemethyl.

83. Method of treating or preventing diabetes, such as type II diabetes,and its complications, such as arthritis, chronic kidney disease andsyndrome X, comprising administration of a PPAR gamma agonist and anNrf2 activator to a patient in need thereof, wherein said Nrf2 activatoris capable of provoking or inducing a stimulated and/or increasednuclear translocation of Nrf2 protein and is:

a) selected from the group of Michael reaction acceptors, phenols,diphenols, chalcones, isothiocyanates, thiocarbamates, quinones,naphthoquinones and 1,2-dithiole-3-thiones; and

b) contains less than 35 carbon atoms; and/or

c) has a molecular weight of less than 600 g/mol; and/or

d) contains no or not more than one or two fused or monocyclic 5- or6-membered carbocyclic or heterocyclic rings having 1, 2 or 3 ring atomsselected from N, O or S.

In one embodiment of the foregoing method, the Nrf2 activator ispreferably other than bardoxolone methyl and/or a corticosteroid.Preferably, the Nrf2 activator is dimethyl fumarate or monomethylhydrogen fumarate.

84. Method of treating or preventing cardiovascular diseases, comprisingadministration of a PPAR gamma agonist and an Nrf2 activator to apatient in need thereof, wherein said Nrf2 activator is capable ofprovoking or inducing a stimulated and/or increased nucleartranslocation of Nrf2 protein and is:

a) selected from the group of Michael reaction acceptors, phenols,diphenols, chalcones, isothiocyanates, thiocarbamates, quinones,naphthoquinones and 1,2-dithiole thiones; and

b) contains less than 35 carbon atoms; and/or

c) has a molecular weight of less than 600 g/mol; and/or

d) contains no or not more than one or two fused or monocyclic 5- or6-membered carbocyclic or heterocyclic rings having 1, 2 or 3 ring atomsselected from N, O or S.

85. Method of treating or preventing respiratory diseases, such asasthma, chronic obstructive pulmonary disorder and fibrosis, comprisingadministration of a PPAR gamma agonist and an Nrf2 activator to apatient in need thereof, wherein said Nrf2 activator is capable ofprovoking or inducing a stimulated and/or increased nucleartranslocation of Nrf2 protein and is:

a) selected from the group of Michael reaction acceptors, phenols,diphenols, chalcones, isothiocyanates, thiocarbamates, quinones,naphthoquinones and 1,2-dithiole-3-thiones; and

b) contains less than 35 carbon atoms; and/or

c) has a molecular weight of less than 600 g/mol; and/or

d) contains no or not more than one or two fused or monocyclic 5- or6-membered carbocyclic or heterocyclic rings having 1, 2 or 3 ring atomsselected from N, O or S.

In one embodiment of the foregoing method, the Nrf2 activator ispreferably other than a corticosteroid. Preferably, the Nrf2 activatoris dimethyl fumarate, monomethyl hydrogen fumarate or bardoloxolonemethyl.

86. Method of treating or preventing graft rejection and/or necrosis,comprising administration of a PPAR gamma agonist and an Nrf2 activatorto a patient in need thereof, wherein said Nrf2 activator is capable ofprovoking or inducing a stimulated and/or increased nucleartranslocation of Nrf2 protein and is:

a) selected from the group of Michael reaction acceptors, phenols,diphenols, chalcones, isothiocyanates, thiocarbamates, quinones,naphthoquinones and 1,2-dithiole-3-thiones; and

b) contains less than 35 carbon atoms; and/or

c) has a molecular weight of less than 600 g/mol; and/or

d) contains no or not more than one or two fused or monocyclic 5- or6-membered carbocyclic or heterocyclic rings, having 1, 2 or 3 ringatoms selected from N, O or S.

87. Method of treating or preventing psoriasis, comprisingadministration of a PPAR agonist and an Nrf2 activator to a patient inneed thereof, wherein said Nrf2 activator is capable of provoking orinducing a stimulated and/or increased nuclear translocation of Nrf2protein and is:

a) selected from the group of Michael reaction acceptors, phenols,diphenols, chalcones, isothiocyanates, thiocarbamates, quinones,naphthoquinones and 1,2-dithiole-3-thiones; and

b) contains less than 35 carbon atoms; and/or

c) has a molecular weight of less than 600 g/mol; and/or

d) contains no or not more than one or two fused or monocyclic 5- or6-membered carbocyclic or heterocyclic rings having 1, 2 or 3 ring atomsselected from N, O or S.

In one embodiment of the foregoing method, no therapeutic amounts ofhydroxyurea are co-administrated to the patient. In another embodimentof the foregoing method, no therapeutic amounts of monomethyl hydrogenfumarate are co-administrated to the patient. In another embodiment ofthe foregoing method, no therapeutic amounts of dimethyl fumarate areco-administrated to the patient. In another embodiment of the foregoingmethod, the Nrf2 activator is bardoloxolone methyl. In anotherembodiment of the foregoing method, the PPAR agonist is other thanpioglitazone, such as rosiglitazone.

88. Method of treating or preventing autoimmune and/or inflammatorydiseases other than psoriasis, comprising administration of a PPARagonist and dialkyl fumarate and/or monoalkyl hydrogen fumarate to apatient in need thereof.

89. Method of treating or preventing autoimmune and/or inflammatorydiseases other than chronic kidney disease, comprising administration ofa PPAR agonist and bardoxolone methyl to a patient in need thereof.

90. Method of treating or preventing cardiovascular diseases,respiratory disorders, graft rejection, cancer and diabetes and itscomplications, comprising administration of a PPAR agonist and dimethylfumarate and/or monomethyl hydrogen fumarate to a patient in needthereof.

91. Method of treating or preventing autoimmune/inflammatory andcardiovascular diseases, respiratory disorders, graft rejection, cancerand diabetes and its complications, comprising administration of a PPARagonist other than pioglitazone and dimethyl fumarate and/or monomethylhydrogen fumarate to a patient in need thereof.

92. PPAR gamma agonist for use in combination with an Nrf2 activator inthe treatment of an autoimmune and/or inflammatory disease.

93. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to one or more of the foregoing embodiments and/or embodiment92, characterized in that the Nrf2 activator is dimethyl fumarate.

94. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to one or more of the foregoing embodiments and/or embodiment92, characterized in that the Nrf2 activator is bardoxolone methyl.

95. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to one of the foregoing embodiments, characterized in that thePPAR gamma agonist is pioglitazone.

96. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to one of the foregoing embodiments, characterized in that thePPAR gamma agonist is selected from the group of rosiglitazone,troglitazone and ciglitazone.

97. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to one of the foregoing embodiments, characterized in that theautoimmune and/or inflammatory disease is psoriasis.

98. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to one of the foregoing embodiments, characterized in that theautoimmune and/or inflammatory disease is multiple sclerosis.

99. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to one of the foregoing embodiments, characterized in that theautoimmune and/or inflammatory disease is ulcerative colitis.

100. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to one of the foregoing embodiments, characterized in that theautoimmune and/or inflammatory disease is Crohn's disease.

101. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to one of the foregoing embodiments, characterized in that theautoimmune and/or inflammatory disease is alopecia areata or cicatricialalopecia.

102. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to one of the foregoing embodiments, characterized in that theautoimmune and/or inflammatory disease is diabetic nephropathy.

103. PPAR gamma agonist for use in combination with an Nrf2 activatoraccording to one of the foregoing embodiments, characterized in that theautoimmune and/or inflammatory disease is myasthenia gravis.

104. A pharmaceutical composition comprising pioglitazone, dimethylfumarate and optionally one or more excipients.

105. A pharmaceutical composition comprising dimethyl fumarate, a PPARgamma agonist selected from rosiglitazone, troglitazone and ciglitazone,and optionally one or more excipients.

106. A pharmaceutical composition comprising bardoxolone methyl, a PPARgamma agonist selected from pioglitazone, rosiglitazone, troglitazoneand ciglitazone, and optionally one or more excipients.

107. Method of treating or preventing neurodegenerative diseases,comprising administration of a PPAR gamma agonist selected from thegroup of glitazones and a fumaric acid monoalkyl and/or dialkyl ester toa patient in need thereof.

108. Method according to one or more of the foregoing embodiments and/orembodiment 107, wherein the fumaric acid dialkyl ester is selected fromdimethyl fumarate and diethyl fumarate and the fumaric acid monoalkylester is selected from monomethyl hydrogen fumarate and monoethylhydrogen fumarate.

109. Method according to one or more of the foregoing embodiments and/orembodiment 107 or 108, wherein the PPAR gamma agonist glitazone isselected from pioglitazone and rosiglitazone.

110. Method according to one or more of the foregoing embodiments and/orembodiment 107, 108 or 109, wherein the neurodegenerative disease ismultiple sclerosis.

111. A pharmaceutical composition comprising a PPAR gamma agonistselected from the group of glitazones, a fumaric acid monoalkyl and/ordialkyl ester and optionally one or more excipients.

112. A pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiment 111, wherein the fumaric aciddialkyl ester is selected from dimethyl fumarate and diethyl fumarateand the fumaric acid monoalkyl ester is selected from monomethylhydrogen fumarate and monoethyl hydrogen fumarate.

113. A pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiment 111 or 112, wherein the PPARgamma agonist glitazone is selected from pioglitazone and rosiglitazone.

114. Method of treating or preventing neurodegenerative diseases,comprising administration of a pharmaceutical composition according toone or more of the foregoing embodiments and/or embodiments 111, 112 or113 to a patient in need thereof.

115. Method according to one or more of the foregoing embodiments and/orembodiment 114, wherein the neurodegenerative disease is multiplesclerosis.

116. A solid oral dosage form comprising a PPAR gamma agonist selectedfrom the group of glitazones, a fumaric acid monoalkyl and/or dialkylester and optionally one or more excipients.

117. A solid oral dosage form according to one or more of the foregoingembodiments and/or embodiment 116, wherein the fumaric acid dialkylester is selected from dimethyl fumarate and diethyl fumarate and thefumaric acid monoalkyl ester is selected from monomethyl hydrogenfumarate and monoethyl hydrogen fumarate.

118. A solid oral dosage form according to one or more of the foregoingembodiments and/or embodiment 116 or 117, wherein the PPAR gamma agonistglitazone is selected from pioglitazone and rosiglitazone.

119. Method of treating or preventing neurodegenerative diseases,comprising oral administration of a solid oral dosage form according toone or more of the foregoing embodiments and/or embodiments 116, 117 or118 to a patient in need thereof.

120. Method according to one or more of the foregoing embodiments and/orembodiment 119, wherein the neurodegenerative disease is multiplesclerosis.

121. Kit of parts comprising: a) a PPAR gamma agonist selected from thegroup of glitazones, b) a fumaric acid monoalkyl and/or dialkyl esterand optionally c) instructions for a dosage regimen.

122. Kit of parts according to one or more of the foregoing embodimentsand/or embodiment 121, wherein the fumaric acid dialkyl ester isselected from dimethyl fumarate and diethyl fumarate and the fumaricacid monoalkyl ester is selected from monomethyl hydrogen fumarate andmonoethyl hydrogen fumarate.

123. Kit of parts according to one or more of the foregoing embodimentsand/or embodiment 121 or 122, wherein the PPAR gamma agonist glitazoneis selected from pioglitazone and rosiglitazone.

124. A method of treatment of an autoimmune and/or inflammatory disordercomprising administration of a combination of a PPAR gamma agonistselected from the group of glitazones and a) an isolated Nrf2 activatorselected from the group of fumaric acid esters, bardoxolone methyl(methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, CDDO-Me, RTA 402),ethyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate,2-cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid (CDDO), 1[2-Cyano-3,12-dioxooleana-1,9(11)-dien oyl]imidazole (CDDO-Im),2-cyano-N-methyl-3,12-dioxooleana-1,9(11)-dien-28 amide (CDDO-methylamide, CDDO-MA), [(±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b, 7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile] (TBE-31),2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile (TP-225),3-tert-butyl-4-hydroxyanisole, 2-tert-butyl-4-hydroxyanisole (BHA),tert-butylquinone (tBQ), tert-butylhydroquinone (tBHQ),3,5-di-tert-butyl-4-hydroxytoluene (BHT),2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadien-1-one(2,6-Di-tert-butylquinone methide, BHT-quinone methide), ethoxyquin,gallic acid esters, auranofin, curcumin, resveratrol, menadione,cinnamic aldehyde, cinnamic acid esters, caffeic acid esters, cafestol,kahweol, lycopene, carnosol, sulforaphane, oltipraz,5-(4-methoxy-phenyl)-1,2-dithiole-3-thione (ADT), sulfasalazine,5-aminosalicylic acid (mesalamine), 5-amino-2-hydroxy-benzoic acid4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenyl ester (ATB-429), allicin,allylisothiocyanate, zerumbone, phenethyl isothiocyanate, benzylisothiocyanate, and 6-methylsulfinylhexyl isothiocyanate as well asalkyl and alkanoyl esters, alkyl ethers, stereoisomers, tautomers andsalts of the aforementioned agents, or b) a pharmaceutical compositioncomprising said isolated Nrf2 activator, provided that if the autoimmuneand/or inflammatory disorder is psoriasis, the PPAR agonist ispioglitazone and the Nrf2 activator is a fumaric acid ester, thetreatment is not combined with hydroxyurea.

125. A method of treatment of an autoimmune and/or inflammatory disordercomprising administration of a combination of a PPAR gamma agonistselected from the group of glitazones and a) an isolated Nrf2 activatorselected from the group of fumaric acid esters,3-tert-butyl-4-hydroxyanisole, 2-tert-butyl-4-hydroxyanisole (BHA),tert-butylquinone (tBQ), tert-butylhydroquinone (tBHQ),3,5-di-tert-butyl-4-hydroxytoluene (BHT),2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadien-1-one(2,6-Di-tert-butylquinone methide, BHT-quinone methide), ethoxyquin,gallic acid esters, auranofin, curcumin, resveratrol, menadione,cinnamic aldehyde, cinnamic acid esters, caffeic acid esters, cafestol,kahweol, lycopene, carnosol, sulforaphane, oltipraz,5-(4-methoxy-phenyl)-1,2-dithiole-3-thione (ADT), sulfasalazine,5-aminosalicylic acid (mesalamine), 5-amino hydroxy-benzoic acid4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenyl ester (ATB-429), allicin,allylisothiocyanate, zerumbone, phenethyl isothiocyanate, benzylisothiocyanate, and 6-methylsulfinylhexyl isothiocyanate as well asalkyl and alkanoyl esters, alkyl ethers, stereoisomers, tautomers andsalts of the aforementioned agents, or b) a pharmaceutical compositioncomprising said isolated Nrf2 activator, provided that if the autoimmuneand/or inflammatory disorder is psoriasis, the PPAR agonist ispioglitazone and the Nrf2 activator is a fumaric acid ester, thetreatment is not combined with hydroxyurea.

126. A method of treatment according to the aforementioned embodiments,wherein the autoimmune and/or inflammatory disorder is selected frompsoriasis, scleroderma, chronic kidney disease (CKD), neurodegenerativediseases, asthma, chronic obstructive pulmonary disorder (COPD),fibrosis, inflammatory arthritis disease and inflammatory bowel disease(IBD).

127. A method of treatment according to the aforementioned embodiment,wherein the autoimmune and/or inflammatory disorder is aneurodegenerative disease selected from multiple sclerosis, clinicallyisolated syndrome (CIS), amyotrophic lateral sclerosis, Alzheimer'sdisease, Huntington's disease, and Parkinson's disease.

128. A method for the reduction of inflammation in a patient, comprisingadministration of a combination of a PPAR gamma agonist selected fromthe group of glitazones and a) an isolated Nrf2 activator selected fromthe group of fumaric acid esters, bardoxolone methyl (methyl2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, CDDO-Me, RTA 402), ethyl2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate,2-cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid (CDDO), 1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im),2-cyano-N-methyl-3,12-dioxooleana-1,9(11)-dien-28 amide (CDDO-methylamide, CDDO-MA), [(±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile] (TBE-31),2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile (TP-225),3-tert-butyl-4-hydroxyanisole, 2-tert-butyl-4-hydroxyanisole (BHA),tert-butylquinone (tBQ), tert-butylhydroquinone (tBHQ),3,5-di-tert-butyl-4-hydroxytoluene (BHT),2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadien-1-one(2,6-Di-tert-butylquinone methide, BHT-quinone methide), ethoxyquin,gallic acid esters, auranofin, curcumin, resveratrol, menadione,cinnamic aldehyde, cinnamic acid esters, caffeic acid esters, cafestol,kahweol, lycopene, carnosol, sulforaphane, oltipraz,5-(4-methoxy-phenyl)-1,2-dithiole-3-thione (ADT), sulfasalazine,5-aminosalicylic acid (mesalamine), 5-amino-2-hydroxy-benzoic acid4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenyl ester (ATB-429), allicin,allylisothiocyanate, zerumbone, phenethyl isothiocyanate, benzylisothiocyanate, and 6-methylsulfinylhexyl isothiocyanate as well asalkyl and alkanoyl esters, alkyl ethers, stereoisomers, tautomers andsalts of the aforementioned agents, or b) a pharmaceutical compositioncomprising said isolated Nrf2 activator, provided that if theinflammation is occurring with and/or is resulting from psoriasis, thePPAR agonist is pioglitazone and the Nrf2 activator is a fumaric acidester, the treatment is not combined with hydroxyurea.

129. A method for the reduction of inflammation in a patient, comprisingadministration of a combination of a PPAR gamma agonist selected fromthe group of glitazones and a) an isolated Nrf2 activator selected fromthe group of fumaric acid esters, 3-tert-butyl-4-hydroxyanisole,2-tert-butyl-4-hydroxyanisole (BHA), tert-butylquinone (tBQ),tert-butylhydroquinone (tBHQ), 3,5-di-tert-butyl-4-hydroxytoluene (BHT),2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadien-1-one(2,6-Di-tert-butylquinone methide, BHT-quinone methide), ethoxyquin,gallic acid esters, auranofin, curcumin, resveratrol, menadione,cinnamic aldehyde, cinnamic acid esters, caffeic acid esters, cafestol,kahweol, lycopene, carnosol, sulforaphane, oltipraz,5-(4-methoxy-phenyl)-1,2-dithiole-3-thione (ADT), sulfasalazine,5-aminosalicylic acid (mesalamine), 5-amino-2-hydroxy-benzoic acid4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenyl ester (ATB-429), allicin,allylisothiocyanate, zerumbone, phenethyl isothiocyanate, benzylisothiocyanate, and 6-methylsulfinylhexyl isothiocyanate as well asalkyl and alkanoyl esters, alkyl ethers, stereoisomers, tautomers andsalts of the aforementioned agents, or b) a pharmaceutical compositioncomprising said isolated Nrf2 activator, provided that if theinflammation is occurring with and/or is resulting from psoriasis, thePPAR agonist is pioglitazone and the Nrf2 activator is a fumaric acidester, the treatment is not combined with hydroxyurea.

130. A method according to the aforementioned embodiments, wherein theinflammation is a chronic inflammation.

131. A method according to the aforementioned embodiments, wherein thePPAR gamma agonist glitazone is selected from pioglitazone androsiglitazone.

132. A method according to the aforementioned embodiments, wherein theNrf2 activator is a fumaric acid ester selected from dialkyl fumarateand monoalkyl fumarate.

133. A method according to the aforementioned embodiment, wherein theNrf2 activator is dimethyl fumarate.

134. A pharmaceutical composition comprising a PPAR gamma agonistselected from the group of glitazones and an Nrf2 activator selectedfrom the group of fumaric acid esters, bardoxolone methyl (methyl2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, CDDO-Me, RTA 402), ethyl2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate,2-cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid (CDDO), 1[2-Cyano-3,12-dioxooleana-1,9(11)-dien oyl]imidazole (CDDO-Im),2-cyano-N-methyl-3,12-dioxooleana-1,9(11)-dien-28 amide (CDDO-methylamide, CDDO-MA), [(±)-(4b S, 8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile] (TBE-31),2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile (TP-225),3-tert-butyl-4-hydroxyanisole, 2-tert-butyl-4-hydroxyanisole (BHA),tert-butylquinone (tBQ), tert-butylhydroquinone (tBHQ),3,5-di-tert-butyl-4-hydroxytoluene (BHT),2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadien-1-one(2,6-Di-tert-butylquinone methide, BHT-quinone methide), ethoxyquin,gallic acid esters, auranofin, curcumin, resveratrol, menadione,cinnamic aldehyde, cinnamic acid esters, caffeic acid esters, cafestol,kahweol, lycopene, carnosol, sulforaphane, oltipraz,5-(4-methoxy-phenyl)-1,2-dithiole-3-thione (ADT), sulfasalazine,5-aminosalicylic acid (mesalamine), 5-amino-2-hydroxy-benzoic acid4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenylester (ATB-429), allicin,allylisothiocyanate, zerumbone, phenethyl isothiocyanate, benzylisothiocyanate, and 6-methylsulfinylhexyl isothiocyanate as well asalkyl and alkanoyl esters, alkyl ethers, stereoisomers, tautomers andsalts of the aforementioned agents, and optionally one or moreexcipients.

135. A pharmaceutical composition comprising a PPAR gamma agonistselected from the group of glitazones and an Nrf2 activator selectedfrom the group of fumaric acid esters, 3-tert-butyl-4-hydroxyanisole,2-tert-butyl-4-hydroxyanisole (BHA), tert-butylquinone (tBQ),tert-butylhydroquinone (tBHQ), 3,5-di-tert-butyl-4-hydroxytoluene (BHT),2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadien-1-one(2,6-Di-tert-butylquinone methide, BHT-quinone methide), ethoxyquin,gallic acid esters, auranofin, curcumin, resveratrol, menadione,cinnamic aldehyde, cinnamic acid esters, caffeic acid esters, cafestol,kahweol, lycopene, carnosol, sulforaphane, oltipraz,5-(4-methoxy-phenyl)-1,2-dithiole-3-thione (ADT), sulfasalazine,5-aminosalicylic acid (mesalamine), 5-amino-2-hydroxy-benzoic acid4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenyl ester (ATB-429), allicin,allylisothiocyanate, zerumbone, phenethyl isothiocyanate, benzylisothiocyanate, and 6-methylsulfinylhexyl isothiocyanate as well asalkyl and alkanoyl esters, alkyl ethers, stereoisomers, tautomers andsalts of the aforementioned agents, and optionally one or moreexcipients.

136. A pharmaceutical composition according to the aforementionedembodiments, wherein the PPAR gamma agonist glitazone is selected frompioglitazone and rosiglitazone.

137. A pharmaceutical composition according to the aforementionedembodiments, wherein the Nrf2 activator is a fumaric acid ester selectedfrom dialkyl fumarate and monoalkyl fumarate.

138. A pharmaceutical composition according to the aforementionedembodiment, wherein the Nrf2 activator is dimethyl fumarate.

139. A solid oral dosage form comprising the pharmaceutical compositionaccording to the aforementioned embodiments.

140. A method of treatment of an autoimmune and/or inflammatory disordercomprising administration of a pharmaceutical composition according toone or more of the foregoing embodiments and/or embodiments 134, 135,136, 137 or 138.

141. A method of treatment according to the aforementioned embodiment,wherein the autoimmune and/or inflammatory disorder is selected frompsoriasis, scleroderma, chronic kidney disease (CKD), neurodegenerativediseases, asthma, chronic obstructive pulmonary disorder (COPD),fibrosis, inflammatory arthritis and inflammatory bowel disease (IBD).

142. A method of treatment according to the aforementioned embodiment,wherein the autoimmune and/or inflammatory disorder is aneurodegenerative disease selected from multiple sclerosis, clinicallyisolated syndrome (CIS), amyotrophic lateral sclerosis, Alzheimer'sdisease, Huntington's disease, and Parkinson's disease.

143. A method for the reduction of inflammation in a patient, comprisingadministration of a pharmaceutical composition according to one or moreof the foregoing embodiments and/or embodiments 134, 135, 136, 137 or138.

144. A method according to the aforementioned embodiment, wherein theinflammation is a chronic inflammation.

145. A kit of parts comprising: a) a PPAR gamma agonist selected fromthe group of glitazones, b) an Nrf2 activator selected from the group offumaric acid esters, bardoxolone methyl (methyl2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, CDDO-Me, RTA 402), ethyl2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate,2-cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid (CDDO),1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im),2-cyano-N-methyl-3,12-dioxooleana-1,9(11)-dien-28 amide (CDDO-methylamide, CDDO-MA), [(±)-(4b5,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile](TBE-31), 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile (TP-225),3-tert-butyl-4-hydroxyanisole, 2-tert-butyl-4-hydroxyanisole (BHA),tert-butylquinone (tBQ), tert-butylhydroquinone (tBHQ),3,5-di-tert-butyl hydroxytoluene (BHT),2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadien-1-one(2,6-Di-tert-butylquinone methide, BHT-quinone methide), ethoxyquin,gallic acid esters, auranofin, curcumin, resveratrol, menadione,cinnamic aldehyde, cinnamic acid esters, caffeic acid esters, cafestol,kahweol, lycopene, carnosol, sulforaphane, oltipraz,5-(4-methoxy-phenyl)-1,2-dithiole-3-thione (ADT), sulfasalazine,5-aminosalicylic acid (mesalamine), 5-amino-2-hydroxy-benzoic acid4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenyl ester (ATB-429), allicin,allylisothiocyanate, zerumbone, phenethyl isothiocyanate, benzylisothiocyanate, and 6-methylsulfinylhexyl isothiocyanate as well asalkyl and alkanoyl esters, alkyl ethers, stereoisomers, tautomers andsalts of the aforementioned agents, and optionally c) instructions for adosing regimen.

146. A kit of parts comprising: a) a PPAR gamma agonist selected fromthe group of glitazones, b) an Nrf2 activator selected from the group offumaric acid esters, 3-tert-butyl-4-hydroxyanisole,2-tert-butyl-4-hydroxyanisole (BHA), tert-butylquinone (tBQ),tert-butylhydroquinone (tBHQ), 3,5-di-tert-butyl-4-hydroxytoluene (BHT),2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadien-1-one(2,6-Di-tert-butylquinone methide, BHT-quinone methide), ethoxyquin,gallic acid esters, auranofin, curcumin, resveratrol, menadione,cinnamic aldehyde, cinnamic acid esters, caffeic acid esters, cafestol,kahweol, lycopene, carnosol, sulforaphane, oltipraz,5-(4-methoxy-phenyl)-1,2-dithiole-3-thione (ADT), sulfasalazine,5-aminosalicylic acid (mesalamine), 5-amino-2-hydroxy-benzoic acid4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenyl ester (ATB-429), allicin,allylisothiocyanate, zerumbone, phenethyl isothiocyanate, benzylisothiocyanate, and 6-methylsulfinylhexyl isothiocyanate as well asalkyl and alkanoyl esters, alkyl ethers, stereoisomers, tautomers andsalts of the aforementioned agents, and optionally c) instructions for adosing regimen.

147. A kit of parts according to the aforementioned embodiments, whereinthe PPAR gamma agonist glitazone is selected from pioglitazone androsiglitazone.

148. A kit of parts according to the aforementioned embodiments, whereinthe Nrf2 activator is a fumaric acid ester selected from dialkylfumarate and monoalkyl fumarate.

149. A kit of parts according to the aforementioned embodiment, whereinthe Nrf2 activator is dimethyl fumarate.

150. A method of treating multiple sclerosis or clinically isolatedsyndrome (CIS) comprising the administration of a pharmaceuticalcomposition comprising a glitazone and a fumaric acid monoalkyl esterand/or fumaric acid dialkyl ester to a patient having multiple sclerosisor clinically isolated syndrome.

151. The method according to one or more of the foregoing embodimentsand/or embodiment 150, wherein the fumaric acid dialkyl ester isselected from dimethyl fumarate or diethyl fumarate and the fumaric acidmonoalkyl ester is selected from monomethyl hydrogen fumarate ormonoethyl hydrogen fumarate.

152. The method according to one or more of the foregoing embodimentsand/or embodiment 151, wherein the fumaric acid dialkyl ester isdimethyl fumarate.

153. The method according to one or more of the foregoing embodimentsand/or embodiment 150, wherein the glitazone is pioglitazone orrosiglitazone.

154. The method according to one or more of the foregoing embodimentsand/or embodiment 150, wherein said composition comprises a fumaric aciddialkyl ester selected from dimethyl fumarate or diethyl fumarate, theglitazone is pioglitazone or rosiglitazone and said pharmaceuticalcomposition is a solid oral dosage form.

155. The method according to one or more of the foregoing embodimentsand/or embodiment 154, wherein said fumaric acid dialkyl ester isdimethyl fumarate.

156. A pharmaceutical composition comprising a glitazone, a fumaric acidmonoalkyl ester and/or fumaric acid dialkyl ester and, optionally, oneor more excipients.

157. The pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiment 156, wherein the fumaric aciddialkyl ester is selected from dimethyl fumarate or diethyl fumarate andthe fumaric acid monoalkyl ester is selected from monomethyl hydrogenfumarate or monoethyl hydrogen fumarate.

158. The pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiment 156, wherein the glitazone ispioglitazone or rosiglitazone.

159. The pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiment 157, wherein the fumaric aciddialkyl ester is dimethyl fumarate.

160. The pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiment 156, wherein said pharmaceuticalcomposition comprises a solid oral dosage form.

161. The pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiment 156, wherein the fumaric aciddialkyl ester is selected from dimethyl fumarate or diethyl fumarate,the fumaric acid monoalkyl ester is selected from monomethyl hydrogenfumarate or monoethyl hydrogen fumarate, the glitazone is pioglitazoneor rosiglitazone and said pharmaceutical composition is an oral dosageform.

162. The pharmaceutical composition according to one or more of theforegoing embodiments and/or embodiment 161, wherein said fumaric aciddialkyl ester is dimethyl fumarate.

163. The method according to one or more of the foregoing embodimentsand/or embodiment 150, wherein said patient has multiple sclerosis.

164. The method according to one or more of the foregoing embodimentsand/or embodiment 150, wherein said patient has clinically isolatedsyndrome.

165. Method of treating or preventing an autoimmune and/or inflammatorydisorder, comprising administration of a PPAR gamma agonist selectedfrom the group of glitazones and a bardoxolone alkyl to a patient inneed thereof.

166. Method according to one or more of the foregoing embodiments and/orembodiment 165, wherein the bardoxolone alkyl is bardoxolone methyl.

167. Method according to one or more of the foregoing embodiments and/orembodiment 165 or 166, wherein the PPAR gamma agonist glitazone isselected from pioglitazone and rosiglitazone.

168. Method according to one or more of the foregoing embodiments and/orembodiment 165, 166 or 167, wherein the autoimmune and/or inflammatorydisorder is chronic kidney disease.

169. Method according to one or more of the foregoing embodiments and/orembodiment 165, 166 or 167, wherein the autoimmune and/or inflammatorydisorder is multiple sclerosis.

170. A composition comprising: a) a compound selected from auranofin,sulfasalazine or 5-aminosalicylic acid (mesalamine) and b) a glitazone.

171. A composition comprising: a) a compound selected from auranofin,sulfasalazine or 5-aminosalicylic acid (mesalamine) and b) pioglitazone.

172. A composition comprising: a) a compound selected from auranofin,sulfasalazine or 5-aminosalicylic acid (mesalamine) and b)rosiglitazone.

173. A pharmaceutical composition comprising: a) a compound selectedfrom auranofin, sulfasalazine or 5-aminosalicylic acid (mesalamine), b)a glitazone, such as pioglitazone or rosiglitazone, and optionally c)one or more excipients.

174. Method of treating rheumatoid arthritis, comprising administeringthe composition according to embodiments 170 to 173, preferably acomposition comprising a) auranofin or sulfasalazine and b) a glitazone,to a patient.

175. Method of treating a condition selected from inflammatory boweldiseases, such as ulcerative colitis and Crohn's disease, comprisingadministering a composition according to embodiments 170 to 173,preferably a composition comprising sulfasalazine or 5-aminosalicylicacid (mesalamine) and a glitazone, to a patient.

In another embodiment of the present invention, the autoimmune and/orinflammatory disease is an oral cavity inflammation or throatinflammation, such as gingivitis, peridontitis or tonsillitis. In apreferred embodiment, such diseases are preferably treated by rinsingthe oral cavity and/or throat with a solution or applying a gel or acream comprising a PPAR gamma agonist, such as a glitazone, preferablypioglitazone or rosiglitazone, and an Nrf2 activator, such assulforaphane, tert-butylhydroquinone and/or butylated hydroxyanisole orothers mentioned herein, preferably 3-tert-butyl-4-hydroxyanisole,2-tert-butyl-4-hydroxyanisole (BHA), tert-butylquinone (tBQ),tert-butylhydroquinone (tBHQ), 3,5-di-tert-butyl-4-hydroxytoluene (BHT),2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadien-1-one(2,6-Di-tert-butylquinone methide, BHT-quinone methide), ethoxyquin,gallic acid esters, curcumin, resveratrol, menadione, cinnamic aldehyde,cinnamic acid esters, caffeic acid esters, cafestol, kahweol, lycopene,carnosol, sulforaphane, oltipraz,5-(4-methoxy-phenyl)-1,2-dithiole-3-thione (ADT),5-amino-2-hydroxy-benzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenylester (ATB-429), allicin, allylisothiocyanate, zerumbone, phenethylisothiocyanate, benzyl isothiocyanate, or 6-methylsulfinylhexylisothiocyanate as well as alkyl and alkanoyl esters, alkyl ethers,stereoisomers, tautomers and salts of the aforementioned agents. Theabove solution or gel can be based on known conventional excipientformulations, such as aqueous formulation of the agents containingpolyvinylpyrrolidone as an excipient. Moreover, the solution or gel maycontain, in addition to the agents, antibacterials such aschlorhexidine, such as chlorhexidine gluconate, cetylpyridiniumchloride, tin fluoride, hexetidine, benzoic acid and its salts, such assodium benzoate, salicylates, such as methyl salicylate, benzalkoniumchloride, methylparaben and/or domiphen bromide.

Therefore, preferred embodiments of the present invention are solutionsand gels or creams containing a PPAR agonist and preferably a PPAR gammaagonist, such as a glitazone, preferably pioglitazone or rosiglitazone,and an Nrf2 activator, such as sulforaphane, tert-butylhydroquinoneand/or butylated hydroxyanisole or others mentioned herein, inparticular 3-tert-butyl-4-hydroxyanisole, 2-tert-butyl-4-hydroxyanisole(BHA), tert-butylquinone (tBQ), tert-butylhydroquinone (tBHQ),3,5-di-tert-butyl-4-hydroxytoluene (BHT),2,6-Di-tert-butyl-4-methylene-2,5-cyclohexadien-1-one(2,6-Di-tert-butylquinone methide, BHT-quinone methide), ethoxyquin,gallic acid esters, curcumin, resveratrol, menadione, cinnamic aldehyde,cinnamic acid esters, caffeic acid esters, cafestol, kahweol, lycopene,carnosol, sulforaphane, oltipraz,5-(4-methoxy-phenyl)-1,2-dithiole-3-thione (ADT),5-amino-2-hydroxy-benzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3-yl)-phenylester (ATB-429), allicin, allylisothiocyanate, zerumbone, phenethylisothiocyanate, benzyl isothiocyanate, and 6-methylsulfinylhexylisothiocyanate as well as alkyl and alkanoyl esters, alkyl ethers,stereoisomers, tautomers and salts of the aforementioned agents. In afurther preferred embodiment, each of the agents is employed in thesesolutions, gels or creams in an amount of at least 0.1%, preferably atleast 0.5% or at least 1, 2 or 3% (w/w) of the total weight of thesolution, cream or gel.

The role of reactive oxygen species and antioxidants in inflammatorydiseases has been described in the Journal of Clinical PeriodontologyVolume 24, Issue 5, 1997, Pages 287-296.

Animal models for peridontitis and gingivitis are well known in the art,e.g., Journal of Biomedicine and Biotechnology Volume 2011, Article ID754857, 8 pages, doi:10.1155/2011/754857.

In another preferred embodiment of the present invention, the PPAR gammaagonist, such as pioglitazone or rosiglitazone, is administered with theNrf2 activator capsaicin for the treatment of an autoimmune and/orinflammatory disorder such as psoriasis, psoriatic arthritis, andarthritis, such as rheumatoid arthritis. The combination can also beused for the treatment of pain, such as neuropathic pain. Combinationswith capsaicin are preferably applied topically in the form of a cream,gel or patch. More preferably the invention relates to a cream, gel orpatch comprising capsaicin and a PPAR gamma agonist, such as aglitazone, preferably pioglitazone or rosiglitazone.

The cream, gel or patch comprising capsaicin according to the inventionprovides advantageous results when topically applied in the animalmodels for psoriasis and rheumatoid arthritis as described herein. Inthese animal models, the cream, gel or patch comprising capsaicin and aPPAR gamma agonist, such as a glitazone, preferably pioglitazone orrosiglitazone, is applied to the joints or other areas of the skin wheresymptoms are present.

In another preferred embodiment, the Nrf2 activators cromolyn sodium ornedocromil are combined with a PPAR gamma agonist, such as a glitazone,preferably pioglitazone or rosiglitazone, in order to treat or preventan autoimmune and/or inflammatory disease, such as asthma, allergiessuch as seasonal allergy or hay fever, COPD or allergic rhinitis.Preferably, combinations containing cromolyn sodium or any other saltthereof or nedocromil or its salt, such as the sodium salt, as an Nrf2activator are combined with the PPAR agonist in a solution or gel or acream or patch, specifically a solution for inhalation or an eyedropsolution, which comprises conventional excipients.

Pioglitazone can be used in its enantiomerically pure or enriched form,as disclosed in WO 2011015868 and WO2011098746, which is particularlyadvantageous for oral mouth rinses, oral gels, inhalation solutions,eyedrops and topical creams, gels or patches for the treatment of theskin.

Preferably, the PPAR agonist and the Nrf2 activator used in the presentinvention do not belong to the same chemical class of compounds, i.e.,the Nrf2 activator preferably belongs to a different class of compoundsthan the PPAR agonist.

Solid oral dosage forms comprising the inventive combinations for use intreatment of inflammatory and/or autoimmune diseases are preferred.Solid oral dosage forms are well-known in the art and comprise powders,granules, lozenges, capsules and tablets, such as compressed tablets(CT), sugar-coated tablets (SCT), film-coated tablets (FCT),enteric-coated tablets (ECT), multiple compressed tablets (MCT), whichare compressed tablets made by more than one compression cycle, layeredtablets, prepared by compressing an additional tablet granulation on apreviously compressed granulation, press-coated tablets,controlled-release tablets, effervescent tablets, compressedsuppositories, buccal and sublingual tablets, molded tablets (tablettriturates, TT) and hypodermic tablets (HT). Most preferred are solidoral dosage forms that contain both agents together in a singlepharmaceutical composition.

Also preferred is a composition comprising dimethyl fumarate, monomethylfumarate, optionally in form of its zinc, magnesium and/or calciumsalts, and a PPAR agonist. The use of this composition in the treatmentof psoriasis is particularly preferred.

Also preferred is a PPAR gamma agonist for use in combination with anNrf2 activator in the treatment of an autoimmune and/or inflammatorydisease, according to any of the foregoing embodiments, characterized inthat the treatment excludes or does not comprise the administration ofhydroxyurea (hydroxycarbamid), particularly if the PPAR gamma agonistand the Nrf2 activator are not used or administered in admixture or in asingle pharmaceutical formulation containing both agents together.

In one embodiment of the present invention, the autoimmune and/orinflammatory disorder treated according to the present invention ispsoriasis and/or inflammation resulting from or occurring withpsoriasis. Preferably, the inventive treatment combines a glitazone withdimethyl fumarate for treating psoriasis and/or inflammation resultingfrom or occurring with psoriasis. If in this case the glitazone ispioglitazone, particularly if it is not used or administered inadmixture with the Nrf2 activator or in a single pharmaceuticalformulation containing both agents together, the patient to be treatedhas preferably not received therapeutic amounts of hydroxyurea beforethe treatment according to the present invention, is not receivinghydroxyurea concomitantly with the treatment according to the presentinvention, and preferably neither thereafter, while pioglitazone,dimethyl fumarate or their metabolites are still present in the body.Thus, if the autoimmune and/or inflammatory disorder is psoriasis, thePPAR agonist is pioglitazone and the Nrf2 activator is a fumaric acidester, the treatment is preferably not combined with hydroxyurea,particularly if the PPAR gamma agonist and the Nrf2 activator are notused or administered in admixture or in a single pharmaceuticalformulation containing both agents together.

If the autoimmune and/or inflammatory disorder treated according to thepresent invention is psoriasis and/or inflammation resulting from oroccurring with psoriasis, the glitazone is in one embodiment preferablyother than pioglitzaone, such as rosiglitazone, or the Nrf2 activator isother than a fumaric acid ester.

Pioglitazone and rosiglitazone tablets are commercially available andcan be used as such for the combination therapy according to theinvention.

In one embodiment, the preferred tablets are film-coated tabletscontaining rosiglitazone maleate equivalent to rosiglitazone, 2 mg, 4mg, or 8 mg, for oral administration, with the following inactiveingredients: hypromellose 2910, lactose monohydrate, magnesium stearate,microcrystalline cellulose, polyethylene glycol 3000, sodium starchglycolate, titanium dioxide, triacetin, and one or more of thefollowing: synthetic red and yellow iron oxides and talc.

In one embodiment, the preferred tablets for oral administration contain15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with thefollowing excipients: lactose monohydrate NF, hydroxypropylcellulose NF,carboxymethylcellulose calcium NF, and magnesium stearate NF.

Other formulations can be obtained in analogy to U.S. Pat. Nos.6,355,676, 7,976,853 and

Throughout the specification, the term “no significant PPAR gammaagonistic activity” or “no significant PPAR gamma agonistic effect”means that at the therapeutically useful concentration of the Nrf2activator, no therapeutically useful PPAR gamma activation can beobtained or measured.

Throughout the specification, the term “no significant effect on Nrf2”,“no significantly activating effect on Nrf2” or “no significant effecton Nrf2 activity” means that at the therapeutically useful concentrationof the PPAR gamma agonist, no therapeutically useful Nrf2 activation canbe obtained or measured.

The terms “monoalkyl fumarate” and “monoalkyl hydrogen fumarate” areused synonymously, such as “monomethyl fumarate” and “monomethylhydrogen fumarate”.

EXAMPLES Example 1 Preparation of Enteric-Coated Micro-Tablets inCapsules Containing 120.0 mg of Dimethyl Fumarate

Following U.S. Pat. No. 7,320,999, 12,000 kg of dimethyl fumarate arecrushed, mixed and homogenized by means of a sieve 800. Then anexcipient mixture with the following composition is prepared: 17.50 kgof starch derivative (STA-RX® 1500), 0.30 kg of microcrystallinecellulose (Avicel® PH-101), 0.75 kg of PVP (Kollidon® 120), 4.00 kg ofPrimogel®, and 0.25 kg of colloidal silicic acid (Aerosil®). Dimethylfumarate is added to the entire powder mixture, mixed, homogenized bymeans of a sieve 200, processed in the usual manner with a 2% aqueoussolution of polyvinyl pyrrolidone (Kollidon® K25) to obtain a bindergranulate and then mixed in the dry state with the outer phase. Saidouter phase consists of 0.50 kg of Mg stearate and 1.50 kg of talcum.

The powder mixture is compressed in the usual manner into 10 mgmicro-tablet cores.

To achieve resistance to gastric acid a solution of 2.250 kg ofhydroxypropyl methylcellulose phthalate (HPMCP, Pharmacoat® HP 50) isdissolved in portions in a mixture of the following solvents: 13.00 L ofacetone, 13.50 L of ethanol (94 wt. %, denatured with 2% of ketone) and1.50 L of demineralized water. As a plasticizer, castor oil (0.240 kg)is added to the finished solution, which is applied in portions onto themicro-tablet cores in the customary manner.

After drying is completed, a suspension of the following composition isapplied as a film coat in the same apparatus: 0.340 kg of talcum, 0.400kg of titanium (VI) oxide (Kronos RN 56), 0.324 kg of colored lacquer (Lred lacquer 86837), 4.800 kg of Eudragit E 12.5% and 0.120 kg ofpolyethylene glycol 6000, pH 11 XI in a solvent mixture of the followingcomposition: 8.170 kg of 2-propanol, 0.200 kg of demineralized water and0.600 kg of glycerine triacetate (Triacetin). This procedure resulted inenteric-coated micro-tablets.

Subsequently, the enteric-coated micro-tablets are filled into hardgelatine capsules and are sealed for use according to the invention.

Micro pellets can be obtained similarly according to U.S. Pat. No.7,320,999.

Example 2 Preparation of Tablets Containing Pioglitazone and DimethylFumarate in Separate Tablet Layers

According to U.S. Pat. No. 8,071,130, a mixture of pioglitazonehydrochloride (99.2 g), croscarmellose sodium (13.2 g) and lactose(184.9 g) is granulated by spraying thereon 136.2 g of an aqueoussolution of hydroxypropylcellulose (6.81 g) in a fluid bed granulator(manufactured by Powrex Corp., Model: LAB-1). The resulting granulatedpowder is then granulated by spraying a suspension obtained bydispersing lactose (36 g) in 148.6 g of an aqueous solution ofhydroxypropylcellulose (7.59 g) thereon in a fluid bed granulator(manufactured by Powrex Corp., Model: LAB-1) to obtain pioglitazonehydrochloride-containing granulated powder coated with lactose. To apart (23.18 g) of the granulated powder thus obtained, croscarmellosesodium (0.728 g) and magnesium stearate (0.096 g) are added and mixed toobtain pioglitazone hydrochloride-containing mixed powder. Thepioglitazone hydrochloride-containing mixed powder is compressed in theform of laminate with a powder obtained according to example 1,containing dimethyl fumarate, a starch derivative (STA-RX® 1500),microcrystalline cellulose (Avicel® PH 101), PVP (Kollidon® 120),Primogel®, and colloidal silicic acid (Aerosil®).

Example 3

According to U.S. Pat. No. 7,976,853, hydroxypropyl cellulose (26.4 g,Grade SSL, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at20° C., 8 mPa·s), polyethylene glycol 6000 (1.32 g), titanium oxide(2.64 g) and pioglitazone hydrochloride (16.5 g) are dispersed in water(297 g) to give a coating solution. The enteric-coated micro-tabletsobtained in example 1 are fed in a film coating equipment(Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with theaforementioned coating solution to give a coated preparation.Subsequently, these enteric-coated micro-tablets, which are coated withpioglitazone hydrochloride, are filled into hard gelatine capsules andare sealed for use according to the present invention.

Alternatively, according to example 1, an enteric-coated tabletcontaining the desired amount of dimethyl fumarate can be obtained,followed by a coating with a pioglitazone formulation as describedabove. The tablets can be used as such for the combination treatmentaccording to the invention.

Example 4

A mixture of pioglitazone hydrochloride (99.2 g), croscarmellose sodium(13.2 g) and lactose (184.9 g) is granulated by spraying thereon 136.2 gof an aqueous solution of hydroxypropylcellulose (6.81 g) in a fluid bedgranulator (manufactured by Powrex Corp., Model: LAB-1). The resultinggranulated powder is then granulated by spraying a suspension obtainedby dispersing lactose (36 g) in 148.6 g of an aqueous solution ofhydroxypropylcellulose (7.59 g) thereon in a fluid bed granulator(manufactured by Powrex Corp., Model: LAB-1) to obtain pioglitazonehydrochloride-containing granulated powder coated with lactose. Adesired amount of the granulated powder thus obtained is filled intocapsules containing dimethyl fumarate enteric-coated micro-tabletsobtained according to example 1, which are thereafter sealed.

Example 5

A capsule is filled with a dispersion of 20 mg of amorphous bardoxolonemethyl in methacrylic acid copolymer Type C, USP in a 4/6 weight ratioof bardoxolone methyl to methacrylic acid copolymer Type C, USP havingthe following composition, prepared according to US 2012/022156:

Amorphous bardoxolone methyl as 40% dispersion: 11.36%

SMCC (90LM, silicified microcrystalline cellulose, as listed in the FDAInactive Ingredients Guide): 36.36%

lactose monohydrate: 40.91%

hydroxypropyl methylcellulose: 6.82%

colloidal silicon dioxide: 0.91%

magnesium stearate: 0.91%

sodium lauryl sulfate: 2.73%.

In addition, the capsule is filled with an equivalent of 45 mg ofpioglitazone in the form of its hydrochloride as a granulated powdercoated with lactose obtained according to the first part of example 4.The capsule is thereafter sealed for use.

Alternatively, the bardoxolone methyl containing mixture and thepioglitazone containing mixture can be compressed into a tablet,preferably a layered tablet, wherein the formulations are arranged in alaminar manner. In one embodiment, an enteric coat is applied to thetablet.

General Experimental Protocols

If not mentioned otherwise, treatment in the following animal modelsconsists of, or animals are treated with, dimethyl fumarate andpioglitazone in the form of its hydrochloride, which is dissolved ordispersed in 0.5% methylcellulose/0.1% Tween80 in distilled water andadministered by oral gavage twice daily. Treatment groups are generallyas follows: vehicle alone, dimethyl fumarate alone, pioglitazone aloneor the combination of dimethyl fumarate and pioglitazone. Thecombination according to the invention results in an improved responseto treatment over the vehicle and the respective agents alone.

The effect of the combinations according to the present invention in thetreatment of cancer and preferably hematologic cancers such as CLL andAML, can be found in Blood. 2006 Nov. 15; 108(10):3530-7 and Cancer ResJun. 15, 2010 70; 4949.

Animal Model for Assessing the Therapeutic and Preventive Effect of theCombination of a PPAR Gamma Agonist and an Nrf2 Activator in Oral CavityInflammation and Throat Inflammation Including Gingivitis, Peridontitis,Tonsillites

Specific pathogen-free C3H/HeN mice are infected according to J.Periodontol. 2000 July; 71(7):1167-73 and are treated daily by oralgavage according to the general example with pioglitatzonehydrochloride, sulforaphane or tert-butylhydroquinone or the combinationof pioglitatzone hydrochloride and sulforaphane or pioglitazonehydrochloride and tert-butylhydroquinone. The treatment with thecombinations results in prevention or delayed onset and reduced signs ofinflammation compared to the individual agents and compared tonon-treated animals. Similar qualitative results are obtained byapplying the treatment by daily rinsing the mouths of the animals for 2minutes with a solution of the agents.

Animal Model for Assessing the Therapeutic and Preventive Effect of theCombination of a PPAR Gamma Agonist and an Nrf2 Activator in RheumatoidArthritis

Animals are prepared according to Wilder, R. L. 2001 (Streptococcal CellWall Arthritis) Current Protocols in Immunology. 26:15.10.1-15.10.12 andtreated daily by oral gavage according to the general example withpioglitatzone hydrochloride, dimethyl fumarate or the combination of theagents. The treatment with the combination results in prevention ordelayed onset and reduced signs of arthritis and inflammation comparedto the individual agents and compared to non-treated animals.

Use of an Animal Model to Assess Effect in Treating Psoriasis

The severe combined immunodeficient (SCID) mouse model can be used toevaluate the efficacy of compounds for treating psoriasis in humans(Boehncke, Ernst Schering Res Found Workshop 2005, 50, 213-34; andBhagavathula et al., J Pharmacol Expt 7 Therapeutics 2008, 324(3),938-947).

SCID mice are used as tissue recipients. One biopsy for each normal orpsoriatic volunteer is transplanted onto the dorsal surface of arecipient mouse. Treatment is initiated 1 to 2 weeks aftertransplantation. Animals with the human skin transplants are dividedinto treatment groups. Animals are treated twice daily for 14 days. Atthe end of treatment, animals are photographed and then euthanized. Thetransplanted human tissue along with the surrounding mouse skin issurgically removed and fixed in 10% formalin and samples are obtainedfor microscopy. Epidermal thickness is measured. Tissue sections arestained with an antibody to the proliferation-associated antigen Ki-67and with an anti-human CD3+ monoclonal antibody to detect human Tlymphocytes in the transplanted tissue.

Sections are also probed with antibodies to c-myc and β-catenin. Apositive response to treatment is reflected by a reduction in theaverage epidermal thickness of the psoriatic skin transplants. Apositive response is also associated with reduced expression of Ki-67 inkeratinocytes.

General EAE Animal Model for Assessing Therapeutic Effect of theCombination of a PPAR Gamma Agonist and an Nrf2 Activator for TreatingMultiple Sclerosis

Animals and EAE Induction Female C57BL/6 mice, 8-10 weeks old (HarlanLaboratories, Livermore, Calif.), are immunized subcutaneously in theflank and mid-scapular region with 200 μg of myelin oligodendrocyteglycoprotein peptide (MOG3S-Ss) (synthesized by Invitrogen) emulsified(1:1 volume ratio) with complete Freund's adjuvant (CFA) (containing 4mg/nL Mycobacterium tuberculosis). Emulsion is prepared by thesyringe-extrusion method with two glass Luer-Lok syringes connected by a3-way stopcock. Mice are also given an intraperitoneal injection of 200ng pertussis toxin (List Biological Laboratories, Inc., Campbell,Calif.) on the day of immunization and on day two post-immunization.Mice are weighed and examined daily for clinical signs of experimentalautoimmune encephalomyelitis (EAE). Food and water are provided adlibitum and once animals start to show disease, food is provided on thecage bottom.

Clinical Evaluation

Mice are scored daily beginning on day 7 post-immunization. The clinicalscoring scale is as follows (Miller and Karplus, Current Protocols inImmunology 2007, 15.1.1-15.1.18): 0=normal; 1=limp tail or hind limbweakness (defined by foot slips between bars of cage top while walking);2=limp tail and hind limb weakness; 3=partial hind limb paralysis(defined as no weight bearing on hind limbs but can still move one orboth hind limbs to some extent); 4=complete hind limb paralysis;5=moribund state (includes forelimb paralysis) or death.

Animal Model for Assessing Therapeutic Effect of the Combination of aPPAR Gamma Agonist and an Nrf2 Activator for Treating Multiple Sclerosis

Experiments are conducted on female mice aged 4-6 weeks belong to theC57BL/6 strain weighing 17-20 g. Experimental autoimmuneencephalomyelitis (EAE) is actively induced using >95% pure syntheticmyelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55,MEVGWYRSPFSRVVHLYRNGK, SEQ ID NO: 1). Each mouse is anesthetized andreceives 200 μg of MOG peptide and 15 μg of Saponin extract fromquillaja bark emulsified in 100 μL of phosphate-buffered saline. A 25 μLvolume is injected subcutaneously over four flank areas. Mice are alsointraperitoneally injected with 200 ng of pertussis toxin in 200 μL ofPBS. A second, identical injection of pertussis toxin is given after 48h.

Daily treatment extends from day 26 to day 36 post-immunization.Clinical scores are obtained daily from day 0 post-immunization untilday 60. Clinical signs are scored using the following protocol: 0, nodetectable signs; 0.5, distal tail limpness, hunched appearance andquiet demeanor; 1, completely limp tail; 1.5, limp tail and hindlimbweakness (unsteady gait and poor grip with hindlimbs); 2, unilateralpartial hindlimb paralysis; 2.5, bilateral hindlimb paralysis; 3,complete bilateral hindlimb paralysis; 3.5, complete hindlimb paralysisand unilateral forelimb paralysis; 4, total paralysis of hindlimbs andforelimbs (Eugster et al., Eur J Immunol 2001, 31, 2302-2312).

Inflammation and demyelination are assessed by histology on sectionsfrom the CNS of EAE mice. Mice are sacrificed after 30 or 60 days andwhole spinal cords are removed and placed in 0.32 M sucrose solution at40° C. overnight. Tissues are prepared and sectioned. Luxol fast bluestain is used to observe areas of demyelination. Haematoxylin and eosinstaining is used to highlight areas of inflammation by darkly stainingthe nuclei of mononuclear cells. Immune cells stained with H&E arecounted in a blinded manner under a light microscope. Sections areseparated into gray and white matter and each sector is counted manuallybefore being combined to give a total for the section. T cells areimmunolabeled with anti-CD3+ monoclonal antibody. After washing,sections are incubated with goat anti-rat HRP secondary antibody.Sections are then washed and counterstained with methyl green.Splenocytes isolated from mice at 30 and 60 days post-immunization aretreated with lysis buffer to remove red blood cells. Cells are thenresuspended in PBS and counted. Cells at a density of about 3×10⁶cells/mL are incubated overnight with 20 μg/mL of MOG peptide.Supernatants from stimulated cells are assayed for IFN-γ protein levelsusing an appropriate mouse IFN-γ immunoassay system.

Use of an Animal Model to Assess Effect in Treating Inflammatory BowelDisease

Animal models of inflammatory bowel disease are described by Jurjus etal, J Pharmaocol Toxicol Methods 2004, 50, 81-92; Villegas et al, Int'limmunopharmacol 2003, 3, 1731-1741; and Murakami et al, BiochemicalPharmacol 2003, 66, 1253-1261. For example, the following protocol canbe used to assess the effect of the combination according to the presentinvention for treating inflammatory bowel disease, Crohn's disease andcolitis.

Female ICR mice are used. Mice are divided into treatment groups. Groupsare given either water (control), 5% DSS in tap water at the beginningof the experiment to induce colitis, or treatment. After administeringthe treatment for 1 week, 5% DSS in tap water is also administered tothe groups receiving treatment for 1 week. At the end of the experiment,all mice are killed and the large intestines are removed. Colonic mucosasamples are obtained and homogenized. Proinflammatory mediators (e.g.,IL-1α, IL-1β, TNF-α, PGE2, and PGF2α) and protein concentrations arequantified. Each excised large intestine is histologically examined andthe damage to the colon scored.

Clinical Trial for Assessing Effect in Treating Asthma

Adult subjects (nonsmokers) with stable mild-to-moderate asthma areenrolled (see, e.g., Van Schoor and Pauwels, Eur Respir J 2002, 19,997-1002). A randomized, double-blind, placebo-controlled, two-periodcrossover design is used. Placebo, dimethyl fumarate alone, pioglitazonealone and a combination of dimethyl fumarate and pioglitazone areadministered orally. The combination according to the invention resultsin an improved response to treatment over the vehicle and the agentsalone.

Use of an Animal Model to Assess Effect in Treating Chronic ObstructivePulmonary Disease

An animal model using mice chronically exposed to cigarette smoke can beused for assessing efficacy in treating emphysema (see, e.g., Martoranaet al., Am J Respir Crit Care Med 2005, 172, 848-835; and Cavarra etal., Am J Respir Crit Care Med 2001, 164, 886-890). Six-week oldC57B1/6J male mice are used. In the acute study, the mice are exposedeither to room air or to the smoke of five cigarettes for 20 minutes. Inthe chronic study, the mice are exposed to either room air or to thesmoke of three cigarettes/day for 5 days/week for 7 months.

In the acute study, mice are divided into three groups. These groups arethen divided into five subgroups of 10 mice each as follows: (1) notreatment/air-exposed; (2) no treatment/smoke-exposed; (3) thecombination of dimethyl fumarate and pioglitazone plus smoke-exposed;(4) pioglitazone plus smoke-exposed; and (5) dimethyl fumarate plussmoke-exposed. In the first group, trolox equivalent antioxidantcapacity is assessed at the end of the exposure in bronchoalveolarlavage fluid; in the second group, cytokines and chemokines aredetermined in bronchoalveolar lavage fluid using a commercial cytokinepanel at 4 hours; and in the third group bronchoalveolar lavage fluidcell count is assessed at 24 hours.

Animal Models for Assessing Therapeutic Effect of the Combination of aPPAR Gamma Agonist and an Nrf2 Activator for Treating Parkinson'sDisease MPTP Induced Neurotoxicity

MPTP, or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, is a neurotoxinthat produces a Parkinsonian syndrome in both man and experimentalanimals. Studies of the mechanism of MPTP neurotoxicity show that itinvolves the generation of a major metabolite, MPP+, formed by theactivity of monoamine oxidase on MPTP. Inhibitors of monoamine oxidaseblock the neurotoxicity of MPTP in both mice and primates. Thespecificity of the neurotoxic effects of MPP+ for dopaminergic neuronsappears to be due to the uptake of MPP+ by the synaptic dopaminetransporter. Blockers of this transporter prevent MPP+ neurotoxicity.MPP+ has been shown to be a relatively specific inhibitor ofmitochondrial complex I activity, binding to complex I at the retenonebinding site and impairing oxidative phosphorylation. In vivo studieshave shown that MPTP can deplete striatal ATP concentrations in mice. Ithas been demonstrated that MPP+ administered intrastriatally to ratsproduces significant depletion of ATP as well as increased lactateconcentration confined to the striatum at the site of the injections.Compounds that enhance ATP production can protect against MPTP toxicityin mice.

Mice or rats are treated either with vehicle alone, dimethyl fumaratealone, pioglitazone alone or the combination of dimethyl fumarate andpioglitazone for three weeks before treatment with MPTP. MPTP isadministered at an appropriate dose, dosing interval, and mode ofadministration for 1 week before sacrifice. Control groups receiveeither normal saline or MPTP hydrochloride alone. Following sacrificethe two striata are rapidly dissected and placed in chilled 0.1 Mperchloric acid. Tissue is subsequently sonicated and aliquots analyzedfor protein content using a fluorometer assay. Dopamine,3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) arealso quantified. Concentrations of dopamine and metabolites areexpressed as nmol/mg protein.

Haloperidol-Induced Hypolocomotion

The ability of a compound to reverse the behavioral depressant effectsof dopamine antagonists, such as haloperidol, in rodents is considered avalid method for screening drugs with potential anti-Parkinsonianeffects (Mandhane, et al., Eur. J. Pharmacol 1997, 328, 135-141). Hence,the ability of the treatment to block haloperidol-induced deficits inlocomotor activity in mice can be used to assess both in vivo andpotential anti-Parkinsonian efficacy.

Mice used in the experiments are housed in a controlled environment andallowed to acclimate before experimental use. One and one-half (1.5)hours before testing, mice are administered 0.2 mg/kg haloperidol, adose that reduces baseline locomotor activity by at least 50%. Treatmentis administered a suitably long prior to testing. The animals are thenplaced individually into clean, clear polycarbonate cages with flatperforated lids.

Horizontal locomotor activity is determined by placing the cages withina frame containing a 3×6 array of photocells interfaced to a computer totabulate beam interrupts. Mice are left undisturbed to explore for 1 h,and the number of beam interruptions made during this period serves asan indicator of locomotor activity, which is compared with data forcontrol animals for statistically significant differences.

6-Hydroxydopamine Animal Model

The neurochemical deficits seen in Parkinson's disease can be reproducedby local injection of the dopaminergic neurotoxin 6-hydroxydopamine(6-OHDA) into brain regions containing either the cell bodies or axonalfibers of the nigrostriatal neurons. By unilaterally lesioning thenigrostriatal pathway on only one side of the brain, a behavioralasymmetry in movement inhibition is observed. Althoughunilaterally-lesioned animals are still mobile and capable of selfmaintenance, the remaining dopamine-sensitive neurons on the lesionedside become supersensitive to stimulation. This is demonstrated by theobservation that following systemic administration of dopamine agonists,such as apomorphine, animals show a pronounced rotation in a directioncontralateral to the side of lesioning. The ability of compounds toinduce contralateral rotations in 6-OHDA lesioned rats has been shown tobe a sensitive model to predict drug efficacy in the treatment ofParkinson's disease.

Male Sprague-Dawley rats are housed in a controlled environment andallowed to acclimate before experimental use. Fifteen minutes prior tosurgery, animals are given an intraperitoneal injection of thenoradrenergic uptake inhibitor desipramine (25 mg/kg) to prevent damageto nondopamine neurons. Animals are then placed in an anesthetic chamberand anesthetized using a mixture of oxygen and isoflurane. Onceunconscious, the animals are transferred to a stereotaxic frame, whereanesthesia is maintained through a mask. The top of the head is shavedand sterilized using an iodine solution. Once dry, a 2 cm long incisionis made along the midline of the scalp and the skin retracted andclipped back to expose the skull. A small hole is then drilled throughthe skull above the injection site. In order to lesion the nigrostriatalpathway, the injection cannula is slowly lowered to a position above theright medial forebrain bundle at−3.2 mm anterior posterior,−1.5 mmmedial lateral from the bregma, and to a depth of 7.2 mm below the duramater. Two minutes after lowering the cannula, 6-OHDA is infused at arate of 0.5 μL/min over 4 min, to provide a final dose of 8 μg. Thecannula is left in place for an additional 5 min to facilitate diffusionbefore being slowly withdrawn. The skin is then sutured shut, and theanimal is removed from the sterereotaxic frame and returned to itshousing. The rats are allowed to recover from surgery for two weeksbefore behavioral testing.

Rotational behavior is measured using a rotameter system havingstainless steel bowls (45 cm dia×15 cm high) enclosed in a transparentPlexiglas cover around the edge of the bowl and extending to a height of29 cm. To assess rotation, rats are placed in a cloth jacket attached toa spring tether connected to an optical rotameter positioned above thebowl, which assesses movement to the left or right either aspartial(45°) or full(360°) rotations.

Treatment is given for a suitable period prior to testing. Animals aregiven a subcutaneous injection of a subthreshold dose of apomorphine,and are then placed in the harness. The number of rotations are recordedfor one hour. The total number of full contralateral rotations duringthe hour test period serves as an index of anti-Parkinsonian drugefficacy.

Animal Model for Assessing Therapeutic Effect for Treating Alzheimer'sDisease

Heterozygous transgenic mice expressing the Swedish AD mutant genehAPPK670N, M671L (Tg2576; Hsiao, Learning & Memory 2001, 8, 301-308),are used as an animal model of Alzheimer's disease. Animals are housedunder standard conditions with a 12:12 light/dark cycle and food andwater available ad libitum. Beginning at 9 months of age, mice aredivided into two groups. The groups of animals receive treatment oversix weeks.

Behavioral testing is performed at each drug dose using the samesequence over two weeks in all experimental groups: (1) spatial reversallearning, (2) locomotion, (3) fear conditioning, and (4) shocksensitivity.

Acquisition of the spatial learning paradigm and reversal learning aretested during the first five days of test compound administration usinga water T-maze as described in Bardgett et al., Brain Res Bull 2003, 60,131-142. Mice are habituated to the water T-maze during days 1-3, andtask acquisition begins on day 4. On day 4, mice are trained to find theescape platform in one choice arm of the maze until 6 to 8 correctchoices are made on consecutive trials. The reversal learning phase isthen conducted on day 5. During the reversal learning phase, mice aretrained to find the escape platform in the choice arm opposite from thelocation of the escape platform on day 4. The same performance criteriaand inter-trial interval are used as during task acquisition.

Large ambulatory movements are assessed to determine that the results ofthe spatial reversal learning paradigm are not influenced by thecapacity for ambulation. After a rest period of two days, horizontalambulatory movements, excluding vertical and fine motor movements, areassessed in a chamber equipped with a grid of motion-sensitive detectorson day 8. The number of movements accompanied by simultaneous blockingand unblocking of a detector in the horizontal dimension are measuredduring a one-hour period.

The capacity of an animal for contextual and cued memory is tested usinga fear conditioning paradigm beginning on day 9. Testing takes place ina chamber that contains a piece of absorbent cotton soaked in anodor-emitting solution such as mint extract placed below the grid floor.A 5-min, 3 trial, 80 db, 2800 Hz tone foot shock sequence isadministered to train the animals on day 9. On day 10, memory forcontext is tested by returning each mouse to the chamber withoutexposure to the tone and foot shock, and recording the presence orabsence of freezing behavior every 10 seconds for 8 minutes. Freezing isdefined as no movement, such as ambulation, sniffing or stereotypy,other than respiration.

On day 11, the response of the animal to an alternate context and to theauditory cue is tested. Coconut extract is placed in a cup and the 80 dBtone is presented, but no foot shock is delivered. The presence orabsence of freezing in response to the alternate context is thendetermined during the first 2 minutes of the trial. The tone is thenpresented continuously for the remaining 8 minutes of the trial, and thepresence or absence of freezing in response to the tone is determined.

On day 12, the animals are tested to assess their sensitivity to theconditioning stimulus, i.e., foot shock. Following the last day ofbehavioral testing, animals are anesthetized and the brains removed,post-fixed overnight, and sections cut through the hippocampus. Thesections are stained to image β-amyloid plaques.

Data is analyzed using appropriate statistical methods.

Animal Model for Assessing Therapeutic Effect for Treating Huntington'sDisease

Neuroprotective Effects in a Transgenic Mouse Model of Huntington'sDisease

Transgenic HD mice of the N171-82Q strain and non-transgenic littermatesare treated from 10 weeks of age. The mice are placed on a rotating rod(“rotarod”). The length of time at which a mouse falls from the rotarodis recorded as a measure of motor coordination. The total distancetraveled by a mouse is also recorded as a measure of overall locomotion.Mice showing improved response to treatment with the combination ofdimethyl fumarate and pioglitazone remain on the rotarod for a longerperiod of time and travel farther than mice administered vehicle oreither agent alone.

Malonate Model of Huntington's Disease

A series of reversible and irreversible inhibitors of enzymes involvedin energy generating pathways has been used to generate animal modelsfor neurodegenerative diseases such as Parkinson's and Huntington'sdiseases. In particular, inhibitors of succinate dehydrogenase, anenzyme that impacts cellular energy homeostasis, has been used togenerate a model for Huntington's disease.

In this malonate model for Huntington's disease, treatment isadministered at an appropriate dose, dosing interval, and route to maleSprague-Dawley rats. Treatment is administered for two weeks prior tothe administration of malonate and then for an additional week prior tosacrifice. Malonate is dissolved in distilled deionized water and the pHadjusted to 7.4 with 0.1 M HCl. Intrastriatal injections of 1.5 μL of 3μmol malonate are made into the left striatum at the level of the bregma2.4 mm lateral to the midline and 4.5 mm ventral to the dura. Animalsare sacrificed at 7 days by decapitation and the brains quickly removedand placed in ice cold 0.9% saline solution. Brains are sectioned at 2mm intervals in a brain mold. Slices are then placed posterior side downin 2% 2,3,5-triphenyltetrazolium chloride. Slices are stained in thedark at room temperature for 30 min and then removed and placed in 4%paraformaldehyde, pH 7.3. Lesions, noted by pale staining, are evaluatedon the posterior surface of each section. The measurements are validatedby comparison with measurements obtained on adjacent Nissl stainedsections.

Animal Model for Assessing Therapeutic Effect for Treating AmyotrophicLateral Sclerosis

A murine model of SOD1 mutation-associated ALS has been developed inwhich mice express the human superoxide dismutase (SOD) mutationglycine-alanine at residue 93 (SOD1). These SOD1 mice exhibit a dominantgain of the adverse property of SOD, and develop motor neurondegeneration and dysfunction similar to that of human ALS. The SOD1transgenic mice show signs of posterior limb weakness at about 3 monthsof age and die at 4 months. Features common to human ALS includeastrocytosis, microgliosis, oxidative stress, increased levels ofcyclooxygenase/prostaglandin, and, as the disease progresses, profoundmotor neuron loss. Studies are performed on transgenic miceoverexpressing human Cu/Zn-SOD G93A mutations (B6S JL-TgN (SOD1-G93A) 1Gur) and non-transgenic B6/SJL mice and their wild litter mates. Miceare housed on a 12-hr day/light cycle and (beginning at 45 d of age)allowed ad libitum access to either test compound-supplemented chow, or,as a control, regular formula cold press chow processed into identicalpellets. Genotyping can be conducted at 21 days of age as described inGurney et al., Science 1994, 264(5166), 1772-1775. The SOD1 mice areseparated into groups and treatment is administered for a suitableperiod.

The mice are observed daily and weighed weekly. To assess health statusmice are weighed weekly and examined for changes inlacrimation/salivation, palpebral closure, ear twitch and pupillaryresponses, whisker orienting, postural and righting reflexes and overallbody condition score. A general pathological examination is conducted atthe time of sacrifice.

Motor coordination performance of the animals can be assessed by one ormore methods known to those skilled in the art. For example, motorcoordination can be assessed using a neurological scoring method. Inneurological scoring, the neurological score of each limb is monitoredand recorded according to a defined 4-point scale: 0—normal reflex ofthe hind limbs (animal will splay its hind limbs when lifted by itstail); 1—abnormal reflex of hind limbs (lack of splaying of hind limbswhen animal is lifted by the tail); 2—abnormal reflex of limbs andevidence of paralysis; 3—lack of reflex and complete paralysis; and4—inability to right when placed on the side in 30 seconds or founddead. The primary end point is survival with secondary end points ofneurological score and body weight. Neurological score observations andbody weight are made and recorded five days per week. Data analysis isperformed using appropriate statistical methods. The rotarod testevaluates the ability of an animal to stay on a rotating dowel, allowingevaluation of motor coordination and proprioceptive sensitivity. Theapparatus is a 3 cm diameter automated rod turning at, for example, 12rounds per min. The rotarod test measures how long the mouse canmaintain itself on the rod without falling. The test can be stoppedafter an arbitrary limit of 120 sec. Should the animal fall down before120 sec, the performance is recorded and two additional trials areperformed. The mean time of 3 trials is calculated. A motor deficit isindicated by a decrease of walking time.

In the grid test, mice are placed on a grid (length: 37 cm, width: 10.5cm, mesh size: 1×1 cm²) situated above a plane support. The number oftimes the mice put their paws through the grid is counted and serves asa measure for motor coordination. The hanging test evaluates the abilityof an animal to hang on a wire. The apparatus is a wire stretchedhorizontally 40 cm above a table. The animal is attached to the wire byits forepaws. The time needed by the animal to catch the string with itshind paws is recorded (60 sec max) during three consecutive trials.

Electrophysiological measurements (EMG) can also be used to assess motoractivity condition. Electromyographic recordings are performed using anelectromyography apparatus. During EMG monitoring mice are anesthetized.The measured parameters are the amplitude and the latency of thecompound muscle action potential (CMAP). CMAP is measured ingastrocnemius muscle after stimulation of the sciatic nerve. A referenceelectrode is inserted near the Achilles tendon and an active needleplaced at the base of the tail. A ground needle is inserted on the lowerback of the mouse. The sciatic nerve is stimulated with a single 0.2msec pulse at supramaximal intensity (12.9 mA). The amplitude (mV) andthe latency of the response (ms) are measured. The amplitude isindicative of the number of active motor units, while distal latencyreflects motor nerve conduction velocity. The effect of the combinationsaccording to the present invention can also be evaluated using biomarkeranalysis. To assess the regulation of protein biomarkers in SOD1 miceduring the onset of motor impairment, samples of lumbar spinal cord(protein extracts) are applied to ProteinChip arrays with varyingsurface chemical/biochemical properties and analyzed, for example, bysurface enhanced laser desorption/ionization or time of flight massspectrometry. Then, using integrated protein mass profile analysismethods, data is used to compare protein expression profiles of thevarious treatment groups. Analysis can be performed using appropriatestatistical methods.

Animal Model for Assessing Therapeutic Effect in Myasthenia Gravis

Induction and clinical evaluation of EAMG are according to InternationalImmunology, Vol. 10, No. 9, pp. 1359-1365.

B6 and μMT mice are immunized s.c. along the shoulders and back with 20μg AChR with CFA in a total volume of 100 μl, and boosted twice atmonthly intervals with 20 μg of AChR in CFA s.c. at four sites on theshoulders and thighs. The mice are observed every other day in a blindedfashion for signs of muscle weakness characteristic of EAMG. Theclinical symptoms are graded between 0 and 3 (4): 0, no definite muscleweakness; 1, normal strength at rest but weak with chin on the floor andinability to raise the head after exercise consisting of 20 consecutivepaw grips; 2, as grade 1 and weakness at rest; and 3, moribund,dehydrated and paralyzed. Clinical EAMG is confirmed by injection ofneostigmine bromide and atropine sulfate. The mice are grouped andtreatment is administered for a suitable period before testing.

Animal Model for Assessing the Therapeutic Effect in Alopecia

The Dundee experimental bald rat (DEBR) and the C3H/HeJ mouse arewell-established animal models for alopecia areata and can be used forthe study of genetic aspects, pathogenesis and therapy of the disease.In C3H/HeJ mice alopecia areata can be experimentally induced bygrafting lesional skin from an affected mouse to a histocompatiblerecipient, which offers the possibility to study the influence ofvarious factors on the development of the disease. The mice are groupedand treatment is administered for a suitable period before testing.

General Experimental Protocol

Treatment in the following animal models consists of dimethyl fumaratedissolved or dispersed in 0.5% Hydroxypropylmethylcellulose (HPMC) K4M/0.25% Tween 20 and pioglitazone dissolved or dispersed in kleptose indistilled water. Treatments were administered by oral gavage once ortwice daily. Treatment groups were generally as follows: appropriatevehicles, dimethyl fumarate, pioglitazone and the combination ofdimethyl fumarate and pioglitazone. The combination according to theinvention results in an improved response to treatment over the vehicleand the respective agents alone.

EAE Animal Model for Assessing Therapeutic Effect of the Combination ofthe PPAR Gamma Agonist and Nrf2 Activator for Treating MultipleSclerosis

Female C57BL/6 mice between 7-8 weeks old are ordered (Janvier (France)or Charles River) and used between 9-11 weeks after an acclimatizationperiod. Experimental autoimmune encephalomyelitis (EAE) is activelyinduced using >95% pure synthetic myelin oligodendrocyte glycoproteinpeptide 35-55 (MOG35-55,Met-Glu-Val-Gly-Trp-Tyr-Arg-Ser-Pro-Phe-Ser-Arg-Val-Val-His-Leu-Tyr-Arg-Asn-Gly-Lys(SEQ ID NO: 1), Ref SC1272, NeoMPS). Each mouse is anesthetized andreceives a subcutaneous injection of 100 μl of Complete Freund'sAdjuvant (Ref 263810, Difco) emulsion containing 200 μg of MOG35-55 and250 μg of dried and killed M. tuberculosis H37 Ra (Ref 231141, Difco)into the lower back. The emulsion is prepared by the syringe method withtwo syringes connected through a Luer-Lok tube. Mice also receive anintra-peritoneal injection of 300 ng of pertussis toxin (Ref BML-G100,Enzo Lifescience) diluted in 200 μl PBS. Pertussis toxin injection isrepeated 48 hours later. Mice are weighed and examined daily forclinical signs of EAE. Food and water are provided ad libitum.

Clinical Evaluation

Animals were assessed for neurological deficits (clinical score) andweighed daily. The clinical scoring scale is as follows; 0=no signs;0.5=distal limp tail; 1=complete tail paralysis; 1.5=hind limb weakness;2=unilateral partial hind limb paralysis; 2.5=bilateral partial hindlimb paralysis; 3=complete bilateral hind limb paralysis; 3.5=fore limbweakness and complete bilateral hind limb paralysis;4=quadriplegia/moribund; 5=death from EAE.

Results: Assessment of treatment with dimethyl fumarate in combinationwith pioglitazone in the form of its hydrochloride Forty female C57BL/6mice aged 8-9 weeks were immunized according to the EAE protocoldescribed in the Methods section. Mice were sorted into 4 differenttreatment groups (n=10) and received treatment with HPMC 0.5%/Tween200.25% (vehicle for dimethyl fumarate) b.i.d. plus Kleptose 20% (vehiclefor pioglitazone) q.d., dimethyl fumarate 60 mg/kg b.i.d. plus Kleptose20% q.d., pioglitazone 10 mg/kg q.d. plus HPMC 0.5%/Tween20 0.25% b.i.d.or dimethyl fumarate 60 mg/kg b.i.d. plus pioglitazone 10 mg/kg q.d. Forsimplicity, the vehicle treatments were not mentioned in graph legendsand the groups above were named as control, dimethyl fumarate 60 mg/kgbid, pioglitazone 10 mg/kg q.d. and dimethyl fumarate+pioglitazone,respectively. Drug treatment started at day 0 post-immunization. Asshown in FIG. 1A, immunization of C57BL/6 mice with MOG35-55 induceslocomotor disability with the clinical signs arising around day 9post-immunization.

The effect of the combination (dimethyl fumarate+pioglitazone) treatmentsignificantly reduced average daily clinical scores (FIG. 1A). Thecombination efficacy was more pronounced and statistically differentfrom the effect of individual treatments. Suppression ofinflammation-induced cachexia acts as a reliable marker of treatmentbenefit. Combination treatment (dimethyl fumarate+pioglitazone)treatment significantly improved body weight in comparison to vehicle orsingle drug treatments (FIG. 1B).

The effect of drug treatment on the prevalence of disease is analysed inFIG. 2 . The onset of disease is defined at the point each mouse firstexhibits a clinical score≥1. FIG. 2A depicts a Kaplan-Meier analysisshowing that control group mice start developing EAE from day 9 withcomplete susceptibility by day 14 post-immunization. The combinationtreatment with dimethyl fumarate+pioglitazone shifted the EAE onsetcurve. Not all animals treated with the drug combination developed signsof disease until the termination of the experiment, i.e., day 22post-immunization. The effect of the combination treatment wasstatistically different not only in comparison with the control group,but also in comparison with each of the drugs dosed alone. FIG. 2B is adifferent representation of the same data. On average, mice treated withvehicle, dimethyl fumarate or pioglitazone alone indistinctly exhibitedthe first clinical signs of disease around day 12-13 post-immunization,whereas in the combination group the average onset of EAE was around day17 post-immunization. The effect of the combination treatment was againstatistically different from and more potent than the other treatedgroups. This data shows that combination treatment results in asynergistic treatment effect which is not observed with individualtreatments.

Gastrointestinal changes including hemorrhage are known side effects ofdimethyl fumarate treatment. Combination treatment and dimethyl fumaratetreatment alone resulted in similar hyperplasia of the macrovilosity ofthe stomach. There was no worsening of symptoms with combinationtreatment. Representative images of the stomachs of mice chronicallytreated for 22 days with dimethyl fumarate, pioglitazone or theirvehicles are shown in FIG. 3 to demonstrate some of these observations.Importantly, the synergistic efficacy discussed in the previousparagraphs was not associated with increased gastrointestinal adverseevents.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 : Combination treatment with dimethyl fumarate+pioglitazone issignificantly more efficacious than each individual drug as stand-alonetreatments or treatment with vehicle on mean clinical scores and also onbody weight changes associated with disease. Average clinical scores (A)and percentage body weight changes (B) of MOG35-55 mice treated withvehicle, dimethyl fumarate, pioglitazone or a combination of both drugsfrom day 0 post-immunization. Kruskal-Wallis (non-parametric ANOVA) withDunn's multiple test correction was applied in A and Student's t-test inB. Horizontal bars represent P<0.05 where λ compares combinationtreatment versus vehicle, Ψ combination treatment versus dimethylfumarate and Φ combination treatment versus pioglitazone.

FIG. 2 : Combination treatment with dimethyl fumarate+pioglitazonecauses a delay in the onset of disease in comparison with eachindividual drug as stand-alone treatments or treatment with vehicle.Kaplan-Meier analysis of the disease prevalence curves (A) and averageday of onset of disease (B) of MOG35-55 mice treated with vehicle,dimethyl fumarate, pioglitazone or a combination of both drugs from day0 post-immunization. The onset of disease was defined as the day micefirst exhibit a clinical score≥1. Gehan-Breslow-Wilcoxon test wasapplied in A and Kruskal-Wallis followed by Dunn's multiple testcorrection in B. Horizontal bars represent P<0.05 where X comparescombination treatment versus vehicle, Ψ combination treatment versusdimethyl fumarate and t combination treatment versus pioglitazone.

FIGS. 3A-3E: Alteration in the macroscopical appearance of the stomachsof mice chronically treated with dimethyl fumarate, but not withpioglitazone or vehicle. Forty C57BL/6 mice immunized with MOG35-55 andtreated by oral gavage for 22 days with a combination ofHPMC0.5%/Tween20 0.25% b.i.d. plus Kleptose 20% q.d. (A, FIG. 3A),dimethyl fumarate 60 mg/kg b.i.d. plus Kleptose 20% q.d. (B),pioglitazone 10 mg/kg q.d. plus HPMC 0.5%/Tween20 0.25% b.i.d. (C, FIG.3C) or dimethyl fumarate 60 mg/kg b.i.d. plus pioglitazone 10 mg/kg q.d.(D, FIG. 3D). An additional group of five mice were sham-immunized(emulsion without MOG35-55) and treated with HPMC0.5%/Tween20 0.25%b.i.d. plus Kleptose 20% q.d. (E, FIG. 3E). Throughout the length of theexperiment three mice were either sacrificed due to humane end-points orsuccumbed to disease. The forty-two remaining animals were euthanizedunder pentobarbital terminal anesthesia, the right atrium of the heartwas incised and mice were perfused with 4% paraformaldehyde through theleft ventricle. The stomach of each mouse was dissected by a transectionof the proximal segment of the esophagus and the duodenum then cut openvia a longitudinal incision through the longest possible axis linkingthe remaining stretch of duodenum and the fundus. Each piece was washedwith phosphate buffered saline and open-mounted. The images shown arefrom one representative mouse from each group. Note the normalappearance of stomachs of all groups of mice that were not exposed todimethyl fumarate (A, C, E, FIGS. 3A, 3C, 3E, respectively) and theseemingly pathological increase in macrovilosity of the stomachs ofgroups B and D that were treated with dimethyl fumarate as stand-aloneor combination treatment with pioglitazone, respectively, giving them athickened and rugose appearance (FIGS. 3B and 3D, respectively).

1. (canceled)
 2. A method of ameliorating or delaying the onset of anautoimmune and/or inflammatory disorder or at least one clinical symptomthereof, comprising the administration of a glitazone or a salt formthereof and a fumaric acid ester or salt thereof, wherein the autoimmuneand/or inflammatory disorder is a neurological disorder orneurodegenerative disease.
 3. The method according to claim 2, whereinthe neurodegenerative disease is selected from multiple sclerosis andclinically isolated syndrome (CIS).
 4. The method according to claim 2,wherein the administration is an oral administration.
 5. The methodaccording to claim 2, wherein the glitazone is selected from the groupconsisting of pioglitazone, rosiglitazone and salt forms thereof.
 6. Themethod according to claim 2, wherein the fumaric acid ester is selectedfrom the group of monomethyl fumarate and dimethyl fumarate.
 7. Themethod according to claim 5, wherein the glitazone is pioglitazone or asalt form thereof.
 8. The method according to claim 7, wherein theglitazone is rosiglitazone or a salt form thereof.
 9. The methodaccording to claim 7, wherein the salt form of pioglitazone ispioglitazone hydrochloride.
 10. The method according to claim 7, whereinthe salt form of rosiglitazone is rosiglitazone maleate.
 11. The methodaccording to claim 2, wherein the glitazone is administered in a dailyoral dose of about 15 mg, about 30 mg or about 45 mg and the glitazoneis pioglitazone.
 12. The method according to claim 2, wherein theglitazone is administered as a pharmaceutical composition that comprisesabout 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about22.5 mg or about 25 mg of a glitazone and the glitazone is pioglitazone.13. The method according to claim 2, wherein the fumaric acid ester orsalt thereof is selected from the group consisting of diethyl fumarate,monoethyl fumarate, dimethyl fumarate, monomethyl fumarate and salts andesters thereof.
 14. The method according to claim 2, wherein the afumaric acid ester or salt thereof is dimethyl fumarate and isadministered in a daily oral dose of about 120 mg, about 240 mg, about360 mg, about 480 mg, about 600 mg or about 720 mg.
 15. The methodaccording to claim 2, wherein the fumaric acid ester or salt thereof isadministered as a pharmaceutical composition that comprises about 120mg, about 200 mg or about 240 mg of a fumaric acid ester or salt thereofand the fumaric acid ester is dimethyl fumarate.